Process for the preparation of 5-oxo-11alpha-hydroxy - 3,5 - seco-a-nor-pregnan-3-oic acid - 3,11 lactones and derivatives thereof



United States Patent PROCESS FOR THE PREPARATION OF S-OXO-lla- HYDROXY 3,5 SECO-A-NOR-PREGNAN-S-OIC ACID 3,11 LACTONES AND DERIVATIVES THEREOF Milan Radoje Uskokovic, Upper Montclair, and Thomas Henry Williams, Passaic, N.J., assignors to Hoftmann- La Roche Inc., Nutley, N.J., a corporation of New ersey No Drawing. Original application Oct. 20, 1965, Ser. No. 499,094. Divided and this application June 17, 1968, Ser. No. 737,351

Claims priority, application Switzerland, Nov. 6, 1963, 13,632/63; Republic of South Africa, Mar. 16, 1965, 65/ 1,408

Int. Cl. C07d 9/00; C07c 171/00, 167/02 U.S. Cl. 260-343.2 3 Claims ABSTRACT OF THE DISCLOSURE This invention is directed to a process for the preparation of 1lrx-hydroxy-3,S-seco-A-nor-androstan-3-oic acid- 3,ll-lactones and llot-hydroxy-3,5-seco-A-nor-pregnan-3- oic acid 3,1l-lactones which comprises ozonizing the corresponding lla-hydroxy-4-en-3-one steroids. These intermediate compounds prepared in accordance with the process of this invention may be converted to steroids of the 9;3,l0a-series which are pharmacologicall useful as anabolic and progestational agents.

RELATED APPLICATIONS This application is a division of applicants copending application Ser. No. 499,094, filed Oct. 20, 1965, entitled Intermediates and Processes," which is a continuationin-part of applicants copending application Ser. No. 400,- 206, filed Sept. 29, 1964, entitled Intermediates and Processes, now US. Patent No. 3,412,107.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel chemical intermediates and processes useful in the preparation of steroids. Natural steroids possess a 9a,105-stereochemical configuration. Steroidal compounds possessing the unnatural 9,3,10a-configuration represent a pharmaceutically valuable class of compounds which, even though numerous members are known in the art, cannot be obtained by totally classical chemical means. In fact, the only known methods for obtaining steroids possessing the unnatural 96,10a-configuration involves at least one photochemical reaction. Such photochemical reactions involve irradiation with ultraviolet light of strong intensity for long periods of time and, in comparison with purely chemical reactions, are very inefiicient and give only small yields.

It is an object of the present invention to provide intermediates and processes which enable the preparation of 9B,l0a-steroid without the necessity of proceeding through a photochemical reaction. It is also an object of this invention to provide novel intermediates and processes which will enable the further exploration of steroids having the unnatural 9B,l0a-configuration. It is also an object of this invention to provide novel 9fl,l0a-steroids.

The novel intermediates and processes of this invention are valuable and provide a new synthetic route completely of a classical chemical nature, i.e., involving no photochemical reaction, for converting steroids having the normal configuration into steroidal compounds possessing the unnatural 9;8,10a,configuration.

In one aspect, the novel intermediates and processes 3,499,912 Patented Mar. 10, 1970 ice of this invention enable the preparation of 96,10a-steroids of the androstane series of the formula 1 H3O I MR, Hag H i \i/& l H

wherein R is, individually, selected from the group consisting of hydroxy and lower alkanoyloxy; R is, individually, hydrogen or lower alkyl and R and R taken together, are selected from the group consisting of (17B-OH, I7a-IOW8I' alkaonoic acid lactone) and 0x0; R is selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkanolyloxy; Y is selected from the group consisting or hydrogen and lower alkyl and X is a substituent in the 6- or 7- position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen.

Compounds of Formula I are useful as anabolic agents.

Other 9fi,l0a-androstanes, the preparation of which is enabled by the intermediates and processes of this invention, are of the formulae wherein R R Y and X have the same meaning as above. Compounds of Formula III are useful as progestational agents and compounds of Formula II are useful as anti-androgenic agents.

In another embodiment of this invention, the novel compounds and intermediates provided by this invention enable the preparation of 9fl,l0a-steroids of the 17,6- pregnane series of the formula compounds of formula IV are useful as progestational agents.

Other 9fi,l0a-steroids of the l7fi-pregnane series, preparable from the novel compounds and process of this invention, are of the formula CHz-OH wherein R';,, R Y and X have the same meaning as above.

Compounds of Formula V are useful as salt-retaining agents, i.e. are useful in the treatment of Addisons disease.

As used herein, the term lower alkyl comprehends both straight and branched chain saturated hydrocarbon groups, such as methyl, ethyl, propyl, isopropyl and the like. Similarly, the term lower alkanoyl comprehends groups such as acetyl and the like, and the term lower alkanoyloxy comprehends groups e.g. formyloxy acetoxy and the like. In the same manner, the term lower alkenyl comprehends groups such as vinyl and the like, and the term lower alkynyl comprehends groups such as ethinyl and the like. Halogen comprehends all four halogens, i.e. iodine, bromine, chlorine and fluorine.

The expression (NB-OH, 17a-1ower alkanoic acid lactone) refers to a configuration on the C-l7 carbon atom illustrated as follows:

wherein W is lower alkylene, e.g. polymethylenes such as ethylene, propylene or the like.

With respect to substituents in the 6- and 7-position, preferred compounds are those having hydrogen or lower alkyl in 6- or 7-position, and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of 9,6,l0a-androstanes of Formulae IIII and of 9/3, l0a-l7fi-pregnanes of Formulae IV-V which comprises the hydrogenation of desA-androst-9-en-5-ones or of desA-l7fi-pregn-9-en-5-ones to 93,10,8-des-A-androstan-S-ones or 9,3, IOfi-desA-l7fl-pregnan-5-ones, respectively, followed by condensation with a lower alkyl vinyl ketone with methyl or ethyl vinyl ketone preferred (as well as substitutes therefor such as l-tertiary amino- B-butanone, l-tertiary amino-3-pentanone and quaternary ammonium salts thereof), l-Q-butan-3-one, 1-Q-butan-3- one lower alkylene ketal, l-Q-butan-3-ol, esterified l-Q- butan-3'ol, 1-Q-butan-3-ol ether, l,3-dichlorobut-2-ene, 1,3-dichloropent-2-ene, l-pentan-3-one, 1-Q-pentan-3-one lower alkylene ketal, l-Q-pentan-3-ol, esterified lQ-pentan-3-ol or l-Q-pentan-3-ol ether, which condensation yields the desired 9fl,l0m-steroids The symbol Q is bromine, chlorine or iodine, with the former two being preferred. This invention also provides a number of different methods for the preparation of said desA-androst-9 en-S-one or desA-l7fl-pregn-9-cn-S-one starting materials from natural steroids.

In one embodiment, a steroid of the 3-oxo-androst-4- one or 3-oxo-l7B-pregn-4-ene series is subjected to an oxidative ring opening of the A-ring yielding a 5-oxo 3,S-seco-A-norandrostan-3-oic acid or a 5-oxo-3,5-seco- A-nor-l7B-pregnan3-oic acid, which 3-oic acid can then be converted to a mixture of a IOa-desA-androstan-S-one and a IOfi-desA-androstan-S-one or a mixture of a 1001- desA-l'Ifl-pregnan-S-one and a lOfl-desA-Ufi-pregnan-S- one. The conversion of the 3-oic acid to the desA-compound can be effected either by pyrolysis of a salt of said 3-oic acid or via the enol lactone, i.e. a 4-oxoandrost-5- en-3-one or a 4-oxo-l7fi-pregn-5-en-3-one, which upon reaction with a Grignard reagent gives an aldol, which in turn can be converted into the desired desA-compound. The desA-compound can then be converted into the starting material desA-androst-9-en-5-one or desA-1'7/3-pregn- 9-en-5-one via a two-step sequence of halogenation and dehydrohalogenation.

In another embodiment of this invention, desA-androst- 9-en-5-one or desA-l7fl-pregn-9-en-5-one starting materials can be prepared from ll-hydroxy steroids of the 3-oxo-androst-4-ene or 3-oxo-17B-pregn-4-ene series. This can be effected in a variety of ways. In one approach, an ll-hydroxy group of a steroid of the 3-oxo-androst-4-ene or 3-oxo-17ptregn-4-ene series is converted into a leaving group, for example, a sulfonic acid ester or carboxylic acid ester. Oxidative ring opening of the A-ring of the thus formed ll-(esterified hydroxy)-containing compound yields the corresponding ll-(esterified hydroxy)-5-oxo-3,5-seco-A-norandrostan-3-oic acid or 11- (esterified hydroxy)-5-oxo-3,5seco-A-nor-17fl-pregnan-3- oic acid which upon pyrolysis of a salt of said 3-oic acid yields the desired desA-androst9-en-5-one or desA-l7;3- pregn-9-en-5-one starting material.

A further approach involves formation of an ll-hydroxy-desA-androstan-S-one of ll-hydroxy-desA-Hppregnan-S-one from an ll-hydroxy steroid of the 3-oxoandrost-4-ene or 3-oxo-17B-pregn-4-ene series via an axidative ring opening of the A-ring of said ll-hydroxy steroid which yields an ll-l1ydroxy-5-oxo-A-nor-3,5-secoandrostan-3-oic acid 3,11-lactone or an ll-hydroxy-S-oxo- 3,5-seco-l7/8-pregnan-3-oic acid 3,11-lactone which, in turn is converted into a salt of the corresponding keto acid which salt upon pyrolysis gives the ll-hydroxy-desA-androstan-S-one or ll-hydroxy-desA-l7fi-pregnan-5-one. Esterification of the ll-hydroxy moiety of the so-obtained compound with an acid moiety yields an ll-(esterificd hydroxy)-desA-androstan-5-one or an ll-(esterified hydroxy)-desA-17;8-pregnan-5-one which upon elimination of the leaving group (i.e., the esterified hydroxy moiety) gives the desired desA-androst-9-en-5-one or desA-17tipregn-9-en-S-one starting material. Though, in the above reaction sequence either Ila-OH or Ila-OH starting material steroids can be used, it is preferred to use Ila-OH starting materials.

As will be appreciated from the above discussion, neither the specific reaction steps nor the reaction sequences of this invention involve any modification of substituents found in the 16- and/or l7-position of the starting material natural steroids. However, in order to obtain unnatural 9B,l0ot-steroids of Formulae l-V, it is necessary or desirable to protect certain of the l6 and/or 17-substituents against one or more of the reaction steps involved. It is also convenient to initially protect such a substituent in the starting material natural steroid and mainain the substituent in its protected form throughout the entire reaction sequence, regenerating the desired substituent only when the steroid of Formulae I-V possessing the unnatural 9fi,l0 x-configuration is obtained. On the other hand, it is sometimes convenient to insert a protecting group only before a certain reaction step or sequence of reaction steps. Said protecting group can then be maintained until the final reaction step or can be split off at some intermediate stage. The protecting groups can be inserted and split off by means known per se. The desirability of having protecting groups present will be further discussed below when the specific reaction steps are discussed in detail. The various substituents which are susceptible to being protected are examplified by the 16-hydroxy group in a compound of any of Formulas I-V, the 17fi-hydroxy group in a compound of any of Formulas I-III, the l7a-hydroxy or 20-oxo group in a compound of any of Formulas IV-V, the 2l-hyclroxy group of a compound of Formula V or the l7-oxo group of a compound of Formula I.

The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e., by reaction with a lower alkanediol, to yield a l7-lower alkylene dioxy or 20-lower alkylene dioxy compound, i.e., a 17-ketal or a ZO-ketal.

The l6-hydroxy, l7a-hydroxy, 17B-hydroxy or 2l-hydroxy moieties can be protected by esterification and/or etherification of the hydroxy group. Any available acid which will form an ester that can subsequently be hydrolyzed to regenerate the hydroxy group is suitable. Exemplary acids useful for this purpose are lower alkanoic acids, eg acetic acid, caproic acid, benzoic acid, phosphoric acid and lower alkane dicarboxylic acids, e.g. succinic acid. Also, protection for the l6a-hydroxy, 17a-hydroxy, or 2l-hydroxy substituent can be effected by forming the lower alkyl ortho ester thereof, i.e. 1601,17otor 17:1,2l-l0W6I alkyl ortho esters. A suitable ether protecting group is, for example, the tetrahydropyranyl ether. Others are arylmethyl ethers such as, for example, the benzyl, benzhydryl and trityl ethers, or a-lower alkoxy-lower alkyl ethers, for example, the methoxymethyl, or allylic ethers.

In compounds containing the dihydroxyacetone side chain at C-l7 (for example, compounds of Formula V wherein R is hydroxy), the side chain at (3-17 can be protected by forming the 17,20; 20,2l-bis-methylenedioxy group or by forming a 17,21-acetal or ketal group, or by forming a 17,2l-diester. The 17,21-acetal or ketal and 17,2l-diester hinder the ZO-ketone group and minimize the possibility of its participating in unwanted side reactions. On the other hand, the 17,20; 20,2l-bis-methylenedioxy derivatives actually convert the ketone to a nonreactive derivative. When both a lfia-hydroxy and l 7a-hydroxy substituent are present, these groups can be protected via formation of a l6a,l7a-acetal or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid bydrolysis.

In compounds wherein there is present neither a 17ahydroxy nor 2l-hydroxy substituent but there is present a 20-oxo group, the 2(J-oxo group can be protected via reduction to the corresponding carbinol (hydroxy) group. Thus, for example, the 1'7-acetyl side chain can be protected via conversion to a 17-(u-hydroxy-ethyD-side chain. Regeneration of the l7-acetyl side chain can be simply effected via conventional oxidation means, for example, via oxidation with chromium trioxide in an organic solvent such as glacial acetic acid. Similarly in compounds containing a l7-oxo, this group can be protected by reduction to the corresponding carbinol (hydroxy) group. Thus, the 17-oxo group can be reduced to a l7fi-OH, 17a-H moiety, from which, when desired, the 17-oxo moiety can be regenerated by oxidation, as described above. Furthermore, a ZO-hydroxy or 17,8-hydroxy group, can itself be protected by esterification, for example, with a lower alkanoic acid such as acetic acid, caproic acid, or the like; or by etherification with moieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl, or the like.

The 1611,1701 or l7a,2l-acetals and ketals above discussed can be formed by reacting l6a,l7a-bis-hydroxy or 17a,2l-bis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal (i.e. a lower alkylene glycol acetal or ketal of a suitable aldheyde or ketone) with the moieties sought to be protected.

Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (lower alkanals), such as cyclopentylcarboxaldehyde and cyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkyl ketones, such as dicyclopentyl ketone, dicyclohexyl ketone, and cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxy-phenyl ketone and cyclohexyl rn-tolyl ketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and heptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as l,l,l-trifiuoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fiuorobenzaldehyde), lower alkoxy-benzaldehydes (e.g. o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-cthylbenzaldehyde), di(lower alkyl)-benzaldehydes (e.g. 0-pdimethylbenzaldehyde); monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpro pionaldehyde, fl-phenylpropionaldehyde, 4-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetophenone, a,u,a-trifiuoroacetophenone, propiophenone, butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g. p chloroaoetophenone and p chloropropriophenone); (lower alkoxy) phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone); di-(lower alkoxy) phenyl lower alkyl ketones; hydroxy-phenyl lower alkyl ketones; (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl lower alkyl ketones (o,pxylyl methyl ketone; benzophenone, and mono-or bis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as l-phenyl-3-butanone and l-phenyl-4- pgntanone, and aromatically substituted derivatives there- 0 Especially suitable are those aldehydes or ketones which, with the l6a,l7aor 17a,2l-bis-hydroxy grouping form an acetal or ketal group of the formula wherein P is individually selected from the group consisting of hydrogen and lower alkyl; Q is individually selected from the group consisting of lower alkyl and aryl; and P and Q taken together are lower alkylene.

The term lower alkylene" comprehends polymethylene chains such as tetramethylene and pentamethylene.

In discussing the various starting materials, intermediates and end-products of this invention, the various protecting groups discussed above will not necessarily be specifically mentioned, but it should be understood that mention of any substituent comprehends the various protected forms thereof, unless specifically mentioned to the contrary.

In one embodiment of this invention, compounds of 7 Formulae I through V are prepared from 913,10B-desA- androstan S-ones or 9 3,IOfl-desA-pregnan-S-ones of the formula IIaC wherein X has the same meaning as above and D represents the carbon and hydrogen atoms necessary to complete the steroid D-ring, as well as the atoms in the substituents in the 16- and 17-positions, as defined in Formulae I-V above.

Thus, 9fl,l0a-androstanes of Formula I can be prepared from 9p,IOB-desA-androstan-50nes of the formula IIaC I H X VII wherein R R R and X have the same meaning as above.

VIII

wherein R R and X have the same meaning as above.

Moreover, 9 B,l0tx-l7fi-pregnanes of Formulae IV and V can be prepared from 913,IOB-desA-pregnanfi-ones of Formulae X and XI, respectively.

011.011 =o mo mm x XI wherein R';,, R R and X have the same meaning as above.

The conversion of a 9B,l0 3-desAcompound of Formula VI to a 9,8,l0a-steroid of Formulae l-V (i.e., VlI I, VIII- 11, IX III, X IV and XI V) is effected by condensing the 913,10fi-desA-compound with a compound selected from the group consisting of lower alkyl vinyl ketone (as well as substitutes therefor such as l-tertiary amino-3-butanone, l-tertiary amino-3pentanone and quaternary ammonium salts thereof), 1,3-dichlorobut-2- ene, 1,3-dichloropent-2-ene, l-Q-butan-3-one, l-Q-butan- 3-one lower alkylene ketal, l-Q-butan-3-ol, l-Q-butan-3- ol ether, esterified 1-Q-butan-3-ol, l-Q-pentan-3-one, l-Q- pentan-3-one lower alkylene ketal, l-Q-pentan-3-ol, l-Q- pentan-3-ol ether or esterified l-Q-pentan-3-ol. Q is bromo, chloro or iodo, with the former two being preferred. Methyl vinyl ketone and l-tertiary amino-3-butanone are the preferred reagents, and the former is especially preferred. Prior to the condensation it is desirable to protect the 20-keto group present in compounds of Formulae X and XI, then it is not necessary to protect 1611,1711 or 2l-hydroxy groups which are presents but groups protecting these moieties can be retained through the condensation reaction. tect 16,l7m or Zl-hydroxy groups which are present,

The above indicated substitutes for lower alkyl vinyl kctones are compounds wherein the vinyl moiety is replaced by a moiety of the formula wherein each R is lower alkyl or taken together both Rs are lower alkylene, oxa-lower alkylene or aza-lower alkylene. Such moieties are, for example, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. The quaternary ammonium salts thereof are formed via the utilization of conventional quaternizing agents, for example, lower alkyl or phenyl-lower alkyl (especially benzyl) halides, rnesylates or tosylates.

When a lower alkyl vinyl ketone or substitute therefor, l-Q-butan-3-one or l-Q-pentan-3-one is used as the reaction partner for the condensation, ring closure to ring A (containing a 3-oxo moiety) of the desired 918,10;- steroid of Formulae I-V occurs simultaneously with the condensation. However, when 1,3-dichlorobut-2-ene, 1,3- dichloropent-Zene, l-Q-butan-3-one lower alkylene ketal, l-Q-butan-3-ol, l-Q-butan-3-ol ether, esterified l-Q-butan- 3-01, l-Q-pentan-3-one lower alkylene ketal, l-Q-pentan- 3ol, 1-Q-pentan-3-ol ether, or esterified l-Qpentan-30l is used as the reaction partner a subsequent step to generate the 3-oxo moiety is required. When l-Q-butan-3-ol or l-Q-pentan-3-ol is used as the reaction partner, the oxo moiety can be generated by oxidation and for this purpose, it is suitable to use oxidation means known per se, for example, chromic acid, chromium trioxide in acetic acid or the like. When esterified or etherified l-Q- butan-3-ol or esterified or etherified l-Q-pentan-3-ol is used as the reaction partner, hydrolysis of the esterified or etherified hydroxy group should be effected prior to oxidation. Suitable ester forming moieties are, for example, carboxylic acids, e.g. lower alkanoic acid such as acetic acid, benzoic acid, and the like; and hydrolysis of the reaction products obtained by reacting such l-Q- butan-B-ol or l-Q-pentan-B-ol esters is suitably conducted by alkaline hydrolysis, e.g., via the use of an aqueous alkali metal hydroxide such as aqueous sodium hydroxide. Suitable ethers are, for example, lower alkyl ethers, i.e. B-methoxy, S-ethoxy or the like; and these are suitably hydrolyzed by acid hydrolysis, e.g. via the use of an aqueous mineral acid such as hydrochloric acid, sulfuric acid or the like. When a l-Q-butan-S-one lower alkylene ketal or a l-Q-pentan-B-one lower alkylene ketal is used as the reaction partner, mild acid hydrolysis of the ketal moiety results in generation of the 3-0xo moiety. Finally, when 1,3-dichlorobut-3-ene or 1,3-dichloropent-S-ene is used as the reaction partner, the 3-oxo moiety can be generated by treatment with a concentrated mineral acid, preferably a strong acid such as hydrochloric acid or sulfuric acid. It should be noted, that 1,3- dichlorobut-Z-ene and 1,3-dichloropent-2-ene may be used as reaction partners with compounds of Formulae X and XI, but not with the l7a-lower alkyl, alkenyl or alkynyl compounds of Formulae VIII-IX. As will be apparent, when a reaction partner based on butane (i.e. having a four carbon atom skeleton) is utilized a compound of Formulae I-V wherein Y is hydrogen is obtained. Similarly, when a reaction partner based on pentane is utilized a compound of Formulae I-V wherein Y is methyl is obtained.

In addition to the preparation of compounds of Formulae I-V from compounds of Formulae VI-XI by the use of the above mentioned reaction partners, it is also possible by the procedures of this invention to prepare compounds of Formulae I-V which, in the A-ring, in addition to containing an unsaturation between the 4- and S-positions also contain an unsaturattion between the 1- and 2-positions. Such 1,4-diene products corresponding to the compounds of Formulae rI-V can be prepared from compounds of Formulae VI-XI by condensation of the latter with a reaction partner selected from the group consisting of ethinyl methyl ketone and ethinyl ethyl ketone (as well as substitutes therefor such as fl-tertiary amino-vinyl methyl or ethyl ketone, quaternary ammonium salts thereof, and fl-lower alkoxy-vinyl methyl or ethyl ketone). Condensation to prepare such a 1,4-diene product corresponding to the compounds of Formulae I-V is effected under the same conditions as is the condensation to prepare a compound of Formulae l-V. The so-obtained 1,4-dienes are useful in the same way as the correspondingly substituted 4-ene-comp0unds of Formulae I-V.

The condensation is suitably effected at, below or above room temperature. For example, at the reflux temperature of the reaction medium or at ice temperature C.) or below. Moreover, the condensation is suitably effected in an organic medium. Preferably the solvent is a lower alkanol, such as methanol, isopropanol, tert-butanol, ethanol, or another non-ketonic organic solvent, such as an ether, e.g. dioxane, diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g. benzene, toluene, xylene, organic acid, such as acetic acid, or the like. Lower :11- kanols are the preferred solvents. It is suitable to catalyze the condensation, and this can be efiected via use of a catalyst such as an alkali metal lower alkoxide, for example sodium ethoxide, potassium t-butoxide, sodium tamylate, or the like, alkali metal hydroxide such as sodium, lithium or potassium hydroxide, a quaternary ammonium hydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide such as benzyl trimethyl ammonium hydroxide, para-toluene sulfonic acid, or the like.

When using a substitute for methyl or ethyl vinyl ketone, or for methyl or ethyl ethinyl ketone, the condensation should be effected under alkaline conditions. As indicated above, among such substitutes are l-tertiary amino-B-butanone, l-tertiary amino-3-pentanone and B- tertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary amino groups are dilower alkylamino groups such as dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. Preferred quaternary ammonium salts of such tertiary amino groups are, for example, those formed from lower alkyl halides such as methyl iodide. An exemplary p-lower alkoxy vinyl methyl or ethyl ketone is B-methoxyvinyl ethyl ketone.

One aspect of this invention is the hydrogenation of desA-androst-9-en-5-ones or desA-pregn-9-en-5-ones to 9B,l05-desAandrostan-5-ones of Formulae VII-IX or to 9p,lOfi-desA-pregnan-S-ones of Formulae X-XI. Thus, 9B,l()fl-desA-androstan-S-ones of Formula VII can be prepared via hydrogenation of desA-androst-9-en-5-ones of the formulae wherein R R R and X have the same meaning as above.

Also, 913,lOfi-desA-pregnan-S-oncs of Formulae X and XI can be prepared by hydrogenation of desA-pregn-9-en-5- ones of the formulae CIIr-RJ (5:0 HICI mo H x xv Jr-non 0:0 H;C|

3 H5O H X XVI wherein R;,, R R and X have the same meaning as above. Prior to hydrogenation, the C-20 keto group in compounds of Formulae XV and XVI or C-17 keto group in compounds of Formula XII should be protected either by conversion to the corresponding carbino or by ketalization as described above. The hydrogenation can, however, be effected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting a hydrogen atom in each of the 9- and positions, can also simultaneously effect hydrogenation of other groups in the molecule. For example, the C-- keto group can be hydrogenated to the corresponding carbinol or the C-l7 lower alkenyl group in compounds of Formula XIII or the C-l7 lower alkynyl group in compounds of Formula XIV can be hydrogenated to the corresponding C-17-lower alkyl compounds. Compounds of Formulae VIII and IX can, in turn, be prepared from compounds of Formula VII wherein R and R together are oxo via reaction with a lower alkenyl or lower alkynyl Grignard reagent, with prior protection of the 5-keto group, for example, by forming S-ketals without concurrent blocking of the 17-keto group. In the same manner compounds of Formulae XIII and XIV can be formed from compounds of Formula XII wherein R and R taken together are 0x0.

Formulae XV-XVI is one of the main features of this 2 invention. It is effected by catalytic hydrogenation, suitably using a precious metal catalyst. Suitable precious metal catalysts are palladium, platinum, ruthenium, and rhodium, the latter two being especially preferred. It is particularly advantageous to use rhodium, for example, rhodium on charcoal (or carbon powder, carbon black, or the like) or rhodium on alumina. In contrast to what would be expected, it has been found that such a catalytic hydrogenation of a compound of Formulae XII-XVI gives a substantial yield of a compound of Formulae VI-XV. In fact, it has been found that such catalytic hydrogenation gives a major proportion of a compound of the Formulae VI-XI. This catalytic hydrogenation is suitably effected in an inert organic solvent, for example, a lower alkanol such as methanol or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cyclohexane, hexane, or the like. Lower alkanols are preferred solvents. Moreover, it is suitably conducted in the presence of an acidic or basic catalyst, for example, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or the like, or a mineral acid, for example, a hydrohalic acid, such as hydrochloric acid, or the like, or an organic acid such as a lower alkanoic acid, for

example, acetic acid. The reaction can be conducted at, above or below room temperature, for example, from about 5 C. to about 100 C. However, it is preferably conducted at a temperature between about 0 C. and about C.

As described above, the desA-androst-9-en-5-ones or desA-l7fl-pregn-9-en-5-ones of Formulae XII-XVI can be prepared from natural steroids by a variety of methods. Thus, in one embodiment of this invention said desA- anrost-9-en-5-ones or desA-l7fl-pregn-9-en-5-ones can be prepared from steroids of the 3-oxo-androst-4-ene or 3-oxo-l7fl-pregn-4-ene series by a reaction sequence which involves as a first step an oxidative ring opening of ring A of the natural steroid. For this oxidative ring opening there can be used as starting materials, natural steroids of the 3-oxo-androst-4-ene or 3-oxo-175-pregn-4-ene series of the formula:

XVII

wherein X is a substituent in the 6-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio and lower alkanoylthio or a substituent in the 7-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen, and Z represents the carbon and hydrogen atoms necessary to complete the steroid D-ring, as well as the atoms in the substituents in the 16- and 17- positions as defined in Formulae I, IV, and V above.

The oxidative ring opening of a natural steroid of Formula XVII yields a 5-oxo-3,5-seco-A-norandrostan-3-oic acid or a 5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula wherein X and Z have the same meaning as above.

The oxidative ring opening of the compound of Formula XVII can be performed by a variety of methods. In a preferred embodiment it is effected by ozonolysis. The ozonolysis is suitably carried out in an organic solvent, for example, acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, or the like, or a mixture of two or more of such solvents such as ethyl acetate/ acetic acid, ethyl acetate/methylene chloride, or the like. Moreover, the ozonolysis is advantageously conducted at below room temperature. Thus, it is preferably conducted at a temperature between about C. and about 25 C. The resulting ozonides can be decomposed by conventional means, for example, by treatment with water, hydrogen peroxide in water, acetic acid or ethyl acetate, or the like. The oxidative ring opening of a compound of Formula XVII to a compound of Formula XVIII can also be effected by other oxidation means, for example, by treatment with hydrogen peroxide. It should be noted that an oxidative ring opening by either ozonolysis or by treatment with hydrogen peroxide, does not require protection of any of the substituents at C-l6 or C-l7. However, as stated above, it may be desirable to protect these substituents against some subsequent reaction in the total reaction sequence being practiced. On the other hand, the oxidative ring opening can also be effected by oxidation with chromium trioxide or via treatment with sodium periodate and potassium permanganate in potassium carbonate solution and if these oxidation means are used, it is necessary to protect any secondary hydroxy groups which might be present such as a 16,17,9- or 21- hydroxy group; preferably, for the purpose of this reaction, with non-aromatic protecting groups.

Following the oxidative ring opening of the A-ring, the so-obtained 5-oxo-3,5-seco-A-n0randrostan-3-oic acid or 5-oxo-3,5-seco-A-norpregnan-3oic acid of Formula XVIII is converted into a mixture of a 10tx-desA-androstan-S-one and 10B-desA-androstan-5-one or a mixture of a lOa-desA-pregnan-S-one and a IOfi-desA-pregnan-S-one as illustrated below:

XVIII alkali metal salt of XVIII H3O Hi H Z H Z J I I aC i H3 I I H H H H XIX XX wherein in Formulae XIX and XX, X and Z have the same meaning as above.

The compounds of Formula XIX are wdesA-androstan-S-ones or 10a-desA-pregnan5-ones, depending on the meaning of Z, and the compounds of Formula XX are 1OB-desA-androstan-S-ones or 105-desA-pregnan 5-ones. The conversion of a compound of Formula XVHI into the compounds of Formula XIX and XX is effected by pyrolysis. In effecting the pyrolysis, it is desirable to convert the 3-oic acid of Formula XVIII into a corresponding metal salt, for example, an alkali metal salt such as the sodium or lithium salt. This conversion to a metal salt can be effected prior to pyrolysis, e.g., by treating the acid with sodium hydroxide or in situ during the course of the pyrolysis, e.g., by fusing the 3-oic acid with a mixture of sodium acetate and potassium acetate. The pyrolysis can be conducted at atmospheric pressure or in a vacuum. One preferable embodiment is to conduct the pyrolysis in a vacuum, at a temperature from about 200 C. to about 350 C. in the presence of a proton acceptor, e.g. an alkali metal or alkaline earth metal salt of a Weak organic acid, for example, potassium acetate, sodium acetate, sodium phenyl-acetate, sodium bicarbonate, or the like; especially preferred is a vacuum of from about .001 to about .5 mm. Hg. Accordingly, it is advantageous to conduct the pyrolysis under alkaline conditions, i.e. at a pH greater than 7. The pyrolysis can be effected in solution or by fusion. An especially preferred method of effecting the pyrolysis is by fusion of an alkali metal salt of a weak acid, for example, an or ganic carboxylic acid such as a lower alkanoic acid or a phenyl-lower alkanoic acid such as phenyl-acetic acid. Another method of effecting the pyrolysis is to heat, preferably at atmospheric pressure, a solution of an alkali metal salt, such as the sodium or lithium salt, of a 3-oic acid of Formula XVIII in a basic organic solvent. The basic organic solvent should, of course, be one which is in the liquid state at the temperature at which the pyrolysis is effected. Thus, the pyrolysis can be effected at a temperature up to the boiling point of the basic organic solvent being used. Suitable basic organic solvents are for example, nitrogen containing organic solvents such as piperidine, pyridine, isoquinoline, quinoline, triethanolamine, or the like. When utilizing this approach using a base organic solvent it is suitable to heat to temperature between about 200 C. and about 300 C., and preferably between about 230 C. and about 260 C. A preferred basic organic solvent for the pyrolysis of a salt of a compound of Formula XVIII to compounds of Formulae XIX and XX is quinoline. If a basic organic solvent is used which boils substantially below 200 C. at atmospheric pressure, it is suitable to conduct the pyrolysis in a sealed tube or an autoclave.

HsC

XIX A wherein X and Z have the same meaning as above.

The compounds of Formula XIX can be prepared from compounds of Formula XIX A in the same manner that compounds of Formula XIX are prepared from compounds of Formula XVII, i.e. by oxidative ring opening of the A-ring of a compound of Formula XIX A followed by elimination of the residue of the A-ring, to yield a compound of Formula XIX. The oxidative ring opening of the compound of XIX A can be performed by ozonolysis as described above for the conversion of a compound of Formula XVII to a compound of Formula XVIII. Such ozonolysis of a compound of Formula XIX A yields a compound of the formula XIX B wherein X and Z have the same meaning as above, and

A is a carboxy or formyl.

A compound of Formula XIX B can then be converted to a compound of Formula XIX, This removal of the residue of the A-ring, i.e. decarboxylation and deformylation, can be effected by heating in an acidic or basic medium. It is preferred to heat to the reflux temperature of the medium which is preferably inert organic solvent such as a lower alkanol, e.g. ethanol, dioxane, ether or the like. The decarboxylation and deformylation yields mainly a compound of Formula XIX, but also a minor yield of the corresponding lOfl-isomer of Formula XX.

Compounds of Formula XIX can also be formed from a compound of Formula XVIII via the formation of an enol-laetone of a compound of Formula XVIII, i.e. via the formation of 4-oxo-androst-5-en-3-one or a 4 0x0- pregn-5-en-3-one of the formula:

wherein X and Z have the same meaning as above,

15 which can then be reacted with a Grignard reagent, such as phenyl magnesium bromide or phenyl lithium, to form the resulting aldol of, for example, the formula mo l wherein X and Z have the same meaning as above,

which, upon treatment with an alkali metal hydroxide, such as potassium hydroxide, at an elevated temperature, for example, from about 200 C. to about 240 C., is converted to the corresponding IOa-desA-androstan-S-One or ltla-desA-pregnan-i-one of Formula XIX.

It should be noted that though the pyrolysis of a compound of Formula XVIII yields both the m d-compounds of Formula XX and the IDs-compounds of Formula XIX, and though either of these isomers can be used in the subsequent halogenation and dehydro-halogenation steps of this reaction sequence, it is sometimes preferable to convert the IOfi-compound of Formula XX into the corresponding l0a-compound of Formula XIX. This conversion can be effected by treating a IOB-desA-androstan- 5-one or IOjS-desA-pregnan-S-one of Formula XX with any base capable of producing a carbanion; for example, it is suitable to use an alkali metal lower alkoxide in an organic solvent such as a lower alkanol, for example, sodium ethoxide in an ethanol solution or sodum methoxide in a methanol solution.

The above-discussed conversion via the alkali metal salt and pyrolysis of compounds of Formula XVIII to compounds of Formulas XIX and XX can be effected without protection of any of the substituents which might be present at C-l6 or C-l7. However, if it is desired for either preceding of succeeding reaction steps of the total reaction sequence, the conversion of a compound of Formula XVIII to compounds of Formulas XIX and XX can be effected with protecting groups present on substituents in the C-l6 and C-17 position.

As stated above, the lOa-desA-androstan-S-ones or 100:- desA-pregnan-S-ones of Formula XIX or the IOfl-desA- androstan-S-ones of lOfi-desA-pregnan-S-ones of Formula XX can be converted via a two-step sequence of halogenation and dchydrohalogenation into the desired starting material desA-androst-9-en-5-one or desA-pregn-9- en-S-one of Formulas XII, XV, and XVI.

In a preferred embodiment a l0a-desA-androstan-5- one or a IOwdesA-pregnan-S-Qne of Formula XIX is subjected to the two-step sequence of halogenation and dehydrohalogenation. l-lalogenation of a compound of Formula XIX or a compound of Formula XX yields a mixture of corresponding halogenated compounds including one of the formula H3 C XXIII wherein X and Z have the same meaning as above, and

Hal is a halogen atom (preferably Br or Cl).

Dehydrohalogenation of a compound of Formula XXIII then yields a desired starting material of Formulas XII,

XV and XVI. Keto groups except for the S-keto group, may require protection prior to the halogenation. In the case of compounds of Formulas XIX and XX containing the C-l7 dihydroxyacetone side chain, represented in Formula V wherein R is hydroxy, this protection can be effected by formation of the 17a,20;20,21-bl$- methylenedioxy derivative. In other cases wherein a C-l7 oxo or 0-20 oxo group is present, protection can be cffected by reduction to the corresponding carbinol either directly prior to the halogenation step or prior to some other step in the reaction sequence leading to the compounds of Formulas XIX and XX.

The halogenation can be effected with halogenating agents such as bromine, sulfuryl chloride, or the like. Bromination is especially preferred. The bromination is suitably effected by treatment with bromine at room temperature or below, preferably at ice temperature or below. Suitably it is conducted in an organic medium; for example, an organic acid such as acetic acid; an ether such as an anhydrous ether, dioxane, tetrahydrofuran; a chlorinated organic solvent such as methylene chloride, chloroform, carbon tetrachloride; or the like; with the addition of hydrogen bromide as a catalyst. When effecting halogenation with sulfuryl chloride, it is suitable to use the same type of organic medium as when brominating; and suitable catalysts are, for example, acetic acid, benzoyl peroxide, or the like.

The subsequent dehydrohalogenation of a compound of Formula XXIII is preferably conducted under mild dehydrohalogenating conditions; for example, by the use of an alkali metal carbonate (e.g. lithium carbonate) or an alkali metal halogenide (e.g. a lithium halide) in an organic solvent such as a di-lower alkyl-formamide, or with an organic base such a collidine. pyridine, or the like. The dehydrohalogenation is advantageously conducted at slightly elevated temperatures, for example, from about 50 C. to about 150 C., preferably from about C, to about C.

Separation of the desired product desA--androst9-en- 5-one or desA-pregn-9-en-5-one of Formulas XII, XV and XVI can be effected by conventional means. As indicated above the halogenation procedure may result in halogenated by-products in addition to the desired intermediate of Formula XXIII. Accordingly, the separation is preferably effected after first subjecting the reaction mixture to dehalogenating conditions in order to dehalogenate the halogenated by-products formed by the halogenation procedure, but not dehalogenated by the dehydrohalogenation. Following such dehalogenation the reaction mixture can then easily be separated by conventional means, for example, by column chromatography, to yield the desired compound of Formulas XII, XV, XVI. An exemplary dehalogenation means is treatment with zinc and sodium acetate in an acetic acid solution at an elevated temperature, for example, about 80 C.

In the case of compounds of Formulas XIX and XX which contain a halogen atom on a carbon atom directly adjacent to a keto group, it is preferable to protect such a halogen atom against dehalogenation prior to subjecting the compound of Formulas XIX or XX to the two step sequence of halogenation and dehydrohalogenation of this embodiment. Such a grouping, containing a halogen atom on a carbon atom directly adjacent to a keto group, is illustrated in a compound of Formulas IV or V wherein R or R is halogen. Thus, if 10w or IOB-desA- pregnan-S-one of Formulas XIX or XX containing a 17mor 2l-halo substituent is to be subjected to the halogenation-dehydrohalogenation sequence it is desirable to first efiect protection of the 17w or 21-halo substitutent. This protection can be effected, for example, by ketalization of the 20-oxo group.

As stated above, the desired desA-androst-9-en-5-ones or desA-pregn9-en-5-ones starting materials can also be prepared from steroids of the 3-oxo-androst-4-ene or 3-oxo-l7p-pregn-4-ene series containing an ll-hydroxy 17 substituent. In one embodiment an ll-hydroxy steroid of the formula Inc wherein X and Z have the same meaning as above,

is reacted with an acid or a reactive derivative thereof to form a leaving group in the ll-position. By reactive derivative is meant, for example, a halide, e.g. a chloride, an anhydride, or the like. Though either 115- or llahydroxy starting materials can be used, it is preferable to utilize a-hydroxy compounds of Formula XXIV as starting materials. Prior to the esterification reaction, it is preferable to protect hydroxy groups present in the C-l6, C-17, or C-Zl position. Suitable acids for the esterification of the ll-hydroxy group, which can be used to form a leaving group in the ll-position are inorganic acids such as phosphoric acid, organic carboxylic acids such as anthraquinone fi-carboxylic acid or organic sulfonic acids, for example, toluene-sulfonic acids, especially p-toluene sulfonic acid, lower alkyl-sulfonic acids such as methane-sulfonic acid and nitrophenyl-sulfonic acids, especially p-nitrophenyl-sulfonic acid. Especially preferred as the leaving group in the ll-position is a lower alkylsulfonyloxy group such as the mesoxy group. However, when it is desired to react a compound of Formula XXIV with a sulfonyloxy forming moiety, then a compound of Formula XXIV having an Ila-configuration should be used as a starting material. The above described esterification of ll-hydroxy steroid starting materials of Formula XXIV yields compounds of the formula l I l XXV wherein X and Z have the same meaning as above, and

LO represents the leaving group.

In the next step of this reaction sequence, the so-formed ll-(esterified hydroxy)-compound of Formula XXI is subjected to an oxidative ring opening of the A-ring to yield the corresponding ll-(esterified hydroxy)--oxo- 3,5-seco-A-norandrostan-3-oic acid or ll-(esterified hydroxy)-5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula LO H3O H 2 r w 1 H H HOOO O X XXVI wherein X, Z and LO have the same meaning as above.

pound of Formula XVIII to compounds of the Formulas XIX and XX directly yields the desired desA-androst-9- en-S-one or desA-pregn-9-en-5-one of Formulas XII, XV, XVI. Thus, pyrolysis of a compound of Formula XXVI directly results in elimination of the leaving group in the ll-position as well as a splitting off of the residue of ring A attached to the l0-position. This procedure of starting from an ll-hydroxy steroid (preferably Ila-hydroxy) of Formula XXIV and proceeding through intermediates of Formulas XXV and XXVI to compounds of Formulas XII, XV, XVI, represents a particularly elegant procedure for preparing the latter compounds. An especially preferred method of elfecting the pyrolysis of a salt of a 3-oic acid of Formula XXVI is the method described above wherein the salt of the 3-oic acid is heated in a liquid basic organic solvent. Especially preferred solvents for the pyrolysis of a salt of a compound of Formula XXVI are triethanolamine and quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of a compound of Formula XXVI involves two separate chemical attacks; one being the elimination of the ll-leaving group and the other being the splitting off of the A-ring residue. Instead of effecting these two attacks simultaneously, as described above, it is also possible to effect them sequentially by just prior to formation of the salt, effecting elimination of the leaving group of the compound of Formula XXVI. This elimination yields a A -seco acid of the formula X XXVIA wherein X and Z have the same meaning as above.

The elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula XXVI with either an inorganic or organic acid or base results in the formation of the desired compound of Formula XXVIA. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g. dimethylformamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethylformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the elimination can be conducted without the addition of a separate basic material. Similarly, if the solvent is acidic, then the elimination can be conducted without the addition of a separate acidic material.

After the elimination is effected the A -seco acid product of Formula XXVIA can then be converted to a salt, for example, an alkali metal salt, and the so-formed salt pyrolyzed according to the conditions described above for the pyrolysis of a compound of Formula XXVI to compounds of Formulas XII, XV and XVI.

After the above-described ll-leaving group elimination and A-ring residue splitting, conducted either simultaneously or sequentially, the desired desA-9-en-5-one compounds of Formulas XII, XV and XVI can be isolated by conventional means. However, it has been found par ticularly suitable with compounds of Formulas XV and XVI to isolate by forming the disemicarbazone of the 19 pyrolysis product and then regenerating therefrom the desired 5,20-dione of Formulas XV or XVI, or if the 20-oxo group has been protected, for example, by reduction to a ZO-hydroxy moiety, by forming the semicarbazone at the 5-position and then regenerating therefrom the desired 5-one compound.

In yet another embodiment of this invention starting material ll-hydroxy steroids of Formula XXIV can be directly subjected to an oxidative ring opening of the A-ring by ozonolysis or treatment with hydroxide peroxide, as described above for the oxidative ring opening of the A-ring of a compound of Formula XVII to a compound of Formula XVIII. This oxidative ring opening of the A-ring of a compound of Formula XXIV yields an ll-hydroxy-5-oxo-3,5-seco-A-norandrostan-5-oic acid 3,11-lactone or an l1-hydroxy-3-oxo-3,5-seco-A-norpregman-3 oic acid 3,1 Hactone of the formula XXVII wherein X and Z have the same meaning as above.

l alkali metal salt HO-IM' Horvw x H Z B Z H 0 5 H i it H .L ll

XXVIII XXIX wherein in Formulas XXVIII and XXIX, X and Z have the same meaning as above.

This pyrolysis of an alkali metal salt derived from a com pound of Formula XXVII can be effected under the same conditions as described above for the pyrolysis of a compound of Formula XVIII to compounds of the Formulae XIX and XX. Though either the Hip-compound of Formula XXVIII or the IOa-COIIlpOuIlCl of Formula XXIX can be subjected to the subsequent steps of this reaction sequence, it is suitable to utilize the 10,8-compound of Formula XXVIII. Conversion of the Illa-compound of Formula XXIX to the lOfi-compound of Formula XXVIII can be effected under the same conditions as described above for the conversion of the compound of Formula XX to a compound of Formula XIX.

In the next step of this reaction sequence, the ll-hydroxy compound of Formula XXVIII or of Formula XXIX can be subjected to esterification whereby to convert the ll-hydroxy group to a leaving group in the 11- position. This esterification can be effected with the same acids or acid derivatives and in the same manner as described above for the esterification of a compound of Formula XXIV to a compound of Formula XXV. As in that instance, it is also preferred in the present instance to form a mesoxy leaving group in the ll-position, though, of

course, other leaving groups as described above are useful for the instant purpose. There is thus obtained a compound of the formula X XXX wherein X, Z and LO have the same meanings as above.

The leaving group can then be eliminated from the 11- position of a compound of Formula XXX resulting in a direct formation of a desA-androst-Q-en-S-one or a dcsA- pregn-9-en-5-one of Formulae XII, XV, XVI. This elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is efiected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula XXX with either an inorganic or organic base results in the formation of the desired compound of Formulae XII, XV, XVI. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkylformamides, e.g. dimethyl formamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethyl formamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the elimination can be conducted without the addition of a separate basic material.

In another aspect, compounds of Formula XXX can be prepared from compounds of the formula wherein X, Z and LO have the same meanings as above.

The compounds of Formula XXXA can be prepared from corresponding ll-hydroxy compounds by esterification as described above for the preparation of compounds of Formula XXV from compounds of Formula XXIV. The compounds of Formula XXX can be prepared from compounds of Formula XXXA in the same manner that compounds of Formula XXX are prepared from compounds of Formula XXV, i.e. by oxidative ring opening of the A-ring of a compound of Formula XXXA followed by elimination of the residue of the A ring to yield a compound of Formula XXX. The oxidative ring opening of the compounds of Formula XXXA can be performed by ozonolysis as described above for conversion of a compound of Formula XXV to a compound of Formula 21 XXVI. Such ozonolysis of a compound of Formula XXXA yields a compound of the formula a/ i is H 2 H3O 11006" i H X XXXB wherein X, Z and LO have the same meaning as above.

A compound of Formula XXXB can then be converted to a compound of Formula XXX. This removal of the residue of the A-ring, i.e. decarboxylation, can be effected as described above for the conversion of a compound of Formula XIXB to a compound of Formula XIX.

The compounds of Formulae I-V preparable by the methods of this invention are not only pharmaceutically useful compounds as described above, but also are themselves useful as intermediates for other 9,8,10a-ster0ids; for example, compounds wherein X is hydrogen or lower alkyl can be modified so as to introduce unsaturation between C-6 and C-7. This can be effected by dehydrogenation means, for example, by halogenation followed by dehydrohalogenation or by means of 2,3-dichloro-5,6-dicyanobenzoquinone, according to known methods. Thus, for example, a 9(3,10u-pl'0geSi6IOn of Formula IV wherein X is hydrogen or lower alkyl can be converted to a 919,100:- pregna-4,6-dien3,20-dione.

A further eembodiment of this invention comprises the preparation of 9B,l0a-steroids of Formulae I-V containing an ll-hydroxy substituent. This can be effected by utilizing an 1l-hydroxy-IOa-desA-androstan-S-one or 11- hydroxy-IOa-desA-pregnan-S-One of Formula XXIX or an ll-hydroxy-lOfi-desA-androstan-S-one or ll-hydroxy-lOB- desA-pregnan-S-one of Formula XXVIII as the starting materials. It is preferred in this embodiment to use the IOfl-isomers of Formula XXVIII as starting materials. As a first step in this the ll-hydroxy group of the compound of Formulae XXVIII or XXIX should be protected. This is suitably effected by esterification, preferably with a carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, or the like. Conversion of the soobtained ll-esterified hydroxy compound then yields an 11- (esterified hydroxy)-desA-androst-9-en-5-one (i.e. a compound of Formula XII containing an ll-esterified hydroxy moiety) or an ll-esterified hydroxy-desA-pregn-9- en-S-one (i.e. a compound of Formula XVXVI containing an lla-esterified hydroxy moiety). This conversion can be effected by halogenation followed by dehydrohalogenation, as described above for the conversion of a compound of Formulae XIX or XX to a compound of Formulae XII, XV or XVI. Catalytic hydrogenation of the so-obtained compound of the formula wherein X and Z have the same meaning as above, and E0 is an esterified hydroxy group as described above in this paragraph,

22 yields an ll-esterified hydr0xy-desA-9ti.lOfi-androstan-S- one or ll-esterified hydroxy-desA-9/3,l0/3,pregnan-5-one, of the formula XXXII wherein X, Z and E0 have the same meaning as above.

This hydrogenation can be conducted in the same manner as described above for the hydrogenation of a compound of Formulae XII-XVI to a compound of Formulae VII, X, XI. Also, compounds of Formula XXXII containing a 17-oxo moiety can be converted to a corresponding compound containing a l7B-hydroxy, l7a-lower alkenyl or lower alkynyl moiety by the methods described above. Also, compounds of Formula XXXII can be hydrolyzed to yield corresponding ll-hydroxy compounds of Formula XXXII, i.e. wherein E0 is hydroxy.

Condensation of the so obtained compound of Formula XXXII or the corresponding 17,8-hydroxy, l7a-lower alkenyl or lower alkynyl compound (i.e. a compound of Formula VI containing a free or ll-esterified hydroxy group) then yields the desired end-product 9;9,l0a-steroid of Formulae I-V containing an ll-hydroxy group. Such condensation can be effected as described above for the preparation of a compound of Formulae I-V from a compound of Formulae VIXI. The so-obtained 93,1004- steroids containing an ll-esterified hydroxy group can be hydrolyzed to the corresponding compounds containing an ll-hydroxy group, which latter compounds are themselves useful as intermediates, for example, the ll-hydroxy group can be oxidized by methods known per se to yield corresponding ll-oxo steroids analogous to compounds of Formulas I-V.

The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.g. capsules, tablets, suspensions, solutions, or the like.

The following examples are illustrative of this invention. All temperatures are in degrees Centigrade. The Florisil adsorbent used infra is a synthetic magnesiasilica gel available from the Floridin Company, PO. Box 989, Tallahassee, Fla. (cf. p. 1590, Merck Index, 7th Edition, 1960). 100-200 mesh material was used. The moiety designated by tetrahydropyranyloxy is tetrahydro-IZ- pyranyloxy. When it is stated that a procedure is effected in the cold, it should be understood that it is commenced at 0 C. Throughout this application when compound of the pregnane series are referred to it should be understood that it is compounds of the 17(3-pregnane series that are being referred to, unless specifically indicated to the contrary, and whether or not the compound of the pregnane series is specifically indicated as of the 17fl-series.

Example 1 A solution of 3.2 g. of l7u-ethyltestosterone in 50 ml. methylene chloride and 25 ml. ethyl acetate was ozonized at -70 (acetone-Dry Ice bath) until the solution was blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The syrupy residue was then dissolved in 100 ml. of glacial acetic acid, and after addition of 5 ml. of 30 percent hydrogen peroxide, left for 24 hours at 0-5. Following this time, it was evaporated to dryness, dissolved in 1500 ml. ether, and extracted with 2 N sodium carbonate solution. The alkaline extract was poured in ic cold hydrochloric acid. The resultant crystalline 17a-ethyl-17B-hydroxy-5- oxo-3,5-seco A norandrostan 3 oic acid was filtered,

washed with water and dried. Upon being recrystallized from acetone, it melted at 196197.

Example 2 A solution of 1.5 g. of l7a-ethyl-l7,8-hydroxy-5-oxo- 3,5-seco-A-norandrostan-3-oic acid in 100 ml. of methanol was titrated with 2 N sodium methoxide to the reddish color of phenolphthaleine, and then evaporated to dryness in vacuo, giving as the residue, the sodium salt of 17a-ethyl-l7fl-hydroxy-5-oxo-3,5-seco A norandrostan- 3-oic acid. 5 g. of sodium-phenylacetate was added to the residue, and the mixture pyrolyzed in vacuo ((0.1 mm.) at 285-295", for 2.5 hours, The sublimate was dissolved in acetone, filtered and the filtrate concentrated in vacuo. The resultant syrupy residue was chromatographed on a 60 g. Florisil (adsorbant) column. The fractions eluted with benzene and 0.5 percent ethylacetate in benzene were combined and gave l7tz-ElllYl-l7fi-l'lYdl0XY-l00cdesA-androstamS-one, M.P. 94-95 after recrystallization from petroleum ether. The fractions eluted with 2 percent and 5 percent ethylacetate in benzene were combined and gave l7a-ethyl-l7B-hydroxy-lOfl-desA-androstan 5 one, M.P. 185-1855", after two recrystallizations from petroleum ether.

Example 2a To a solution of 100 mg. of 17a-ethyl-17B-hydroxy-10B- desA-androstan-S-one in 10 ml. of absolute ethanol was added one equivalent of sodium ethoxide dissolved in 5 ml. of absolute ethanol. This reaction mixture was maintained at room temperature overnight, then acidified with glacial acetic acid, poured in water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thin layer chromatography showed the product to be 17a-ethyl-17B-hydroxy-IOa-desA-androstan-S- one. It was obtained crystalline from petroleum etherether and melted at 89-95.

Example 3 1.13 g. of l'lu-ethyl-l7B-hydroxy-l0a-desA-androstan 5-one was dissolved in 120 ml. of anhydrous ether (or 1.13 g. of 10,8isomer was dissolved in 300 ml. of anhydrous ether), and after cooling in a salt-ice bath, several drops of 30 percent hydrobrominic acid in acetic acid were added. This was followed by the drop-wise addition during five minutes of 0.684 g. of bromine dissolved in 2 ml. of acetic acid. This addition was synchronized with the decoloration rate of the reaction mixture. Immediately after this, 5 ml. of a saturated solution of sodium bisulfite and 5 ml. of 2 N sodium carbonate solution were added. The mixture was then transferred into a separatory funnel, 500 ml. of ether added, shaken and separated. The ether part was washed with water, dried and evaporated. The resultant bromides were dissolved in 100 ml. of dimethylformamide, and after addition of 3 g. of lithium carbonate, the solution was heated at 100 for 45 minutes. After cooling, it was poured into one liter of ether, washed with water, 1 N hydrochloric acid, 2 N sodium carbonate. water, dried and evaporated. The residue was dissolved in 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. of zinc powder added, and the so-formed mixture heated 10 minutes at 80". It was then poured into one liter of ethylacetate and the resultant solution washed with saturated sodium bicarbonate, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent)/column. The fraction with benzene and /.1 percent ethylacetate in benzene gave regenerated starting material. Fractions with l and 2 percent ethylacetate in benzene gave 17a-ethyll'l'fi-hydroxy-desA-androst-9-en-5one, which after sublimation (140 and 0.1 mm. Hg vacuum), was obtained as a glass. [a] 36.6 (c. l, CHCl Example 4 A suspension of 262 mg. of 5 percent rhodium on alumina catlayst in a mixture of 26 ml. of percent ethanol and 5.25 ml. of 2 N sodium hydroxide solution was pre-reduced (i.e. hydrogenated at room temperature and atmospheric pressure). To this was added a solution of 262 mg. of 17a-ethyl-l75-hydroxy-desA-androst-Q-en- 5-one in 15 ml. of 95 percent ethanol, and the mixture then hydrogenated at atmospheric pressure and room temperature. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate evaporated in vacuo. Glacial acetic acid (1 ml.) was added to the re sidue, which was then dissolved in 1 liter of ether. The cloudy solution which resulted was washed with 2 N Na CO solution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined products chromatographed on a Florisil (adsorbent) column. The eluates with 1 percent ethyl acetate in benzene gave first crystalline fractions, which were followed by non-crystalline fractions. The non-crystalline fractions were dissolved in ml. of methylene chloride, and after the addition of 2.5 ml. of 2 percent CrO in 90 percent acetic acid, stirred overnight. The excess of chromic acid was removed by washing the methylene chloride solution with 10 ml. of 10 percent sodium hydrogen sulfite solution, followed by washing with 2 N Na CO solution and then with water. It was then dried and evaporated in vacuo. The residue was dissolved in 50 ml. of anhydrous ethanol containing 172 mg. of sodium elhoxide, and left overnight. The next day, after addition of 0.5 ml. of glacial acetic acid, the solution was evaporated in vacuo, and the residue was taken up in 1 liter of ether. The ether solution was washed with 2 N Na CO solution, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column and gave crystalline 17a-Cthyl-l7fihydroxy-desA-9fi,IOB-androstan-S-one identical (by thin layer chromatography) with the crystalline material obtained in the first chromatographic separation. After two recrystallizations from ether, it melted at 142-144"; [M 11.65 (methanol, c.:1.245 percent).

Example 5 To a solution of 132 mg. of 17a-ethyl-l7t3hydroxydesA-96,IOB-androstan-S-one in 12.5 ml. of absolute ethanol containing 34 mg. of sodium ethoxide, 0.15 ml. of freshly distilled methylvinyl ketone was added. The reaction mixture was then refluxed for two hours in a nitrogen atmosphere. After cooling the reaction mixture, 0.1 ml. of glacial acetic acid was added thereto and the resulting mixture was then poured into 1 liter of ether. The resultant ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was chromatographed on fluorescent silica-gel plates, with the solvent system, 60 percent ethyl acetate-40 percent heptane. The fluorescent part of the layers was extracted with ethyl acetate. The residue obtained after evaporation of ethyl acetate was first crystallized from ether-petroleum ether, then a second time from pure ether, yielding 17a-ethyl-9p,mot-testosterone, M.P. 13l135.

Example 6 A solution of 6.4 g. of lla-hydroxy-progesterone in 100 ml. of ethylacetate and 50 ml. of methylene chloride was treated with ozone at 70 until the solution became blue in color. Oxygen was then passed through and the solution evaporated at room temperature in vacuo. The so-obtained syrupy residue was dissolved in 100 ml. of glacial acetic acid, and after the addition of 5 ml. of 30 percent hydrogen peroxide, left for 24 hours at 2' (in an ice box). The solution was then evaporated in vacuo, and the residue triturated with ether yielding crystals. Recrystallization from acetone yielded lla-hydroxy- 3,5-seco A nor pregnane-5,20 dione-3-oic acid 3,11- lactone, M.P. 253256. [a] +1933 (c.=l, in chloroform).

Example 7 A methanolic solution of 7.5 g. of lla-hydroxy-3,S- seco-A-nor-pregnane-S,20-dione-3-oie acid 3,11-lactone was treated with one equivalent of 10 N sodium hydroxide solution and then evaporated to dryness. Sodium phenylacetate (26 g.) was added to the so-obtained sodium salt and the mixture pyrolyzed at 295 for two hours in vacuo. The crude sublimate was chromatographed on a silica-gel column and eluted with 10 percent ethylacetate in benzene. The amorphous solid 1la-hydroxy-10a-desA- pregnane-5,20-dione was first eluted from the column. IR-spectrum in chloroform: 3620 and 3600 cm. (-OH); 1706 cm.- (carbonyl group). NMR-spectrum in deuterochloroform: a doublet for lOu-CH at 73.5 and 80.5 cps. downfield from TMS at 60 mc./sec. Further elution of the column with 10 percent ethylacetate in benzene yielded crystalline 11a-hydroxy-10B-desA- pregnane-5,20-dione which was recrystallized from methylene chloride-petroleum ether, M.P. 150-152"; [(11 +84.0 (c.:0.5 in absolute ethanol).

Example 8 To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml. of pyridine, there was added 100 mg. of 11ahydroxy-10/B-desA-pregnane-5,20-dione. The mixture was then allowed to stand overnight at 2 (in a refrigerator), then was diluted with water (100 ml.) and extracted with chloroform (3X 150 ml.) and methylene chloride (100 mL). The combined organic extracts were washed with water, 1 N hydrochloric acid and again with water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from ether, giving lla-hydroxy-lOfl-desA-pregnane-S,20-dione methanesulfonate, M.P. 139-140"; [111 +46 (c.:0.5 in absolute ethanol).

Example 9 A solution of 200 mg. of IIa-hYdIOXY-IOB-CIESA- pregnane-5,20-dione methanesulfonate in 50 ml. of dimethylformamide was refluxed for eight hours and then evaporated to dryness. The residue was chromatographed on a Florisil (adsorbent) column. Elution with 2 percent ethylacetate/ benzene and evaporation of the eluant yielded desA-pregn-9-ene-5,20-dione in the form of colorless needles, M.P. 1111l3. It was shown by mixed melting point to be identical with a sample of the same compound prepared as described in Example 12.

Example 10 To a solution of g. of lla-hydroxy-progesterone in 150 ml. of pyridine maintained at 0, there was added 6 ml. of methanesulfonylchloride, and the reaction mixture allowed to stand overnight at 0. It was then diluted with a large excess of water and extracted with chloroform. The organic extracts were washed with 2 N hydrochloric acid and water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue was recrystallized from methanol to give lla-mesyloxyprogesterone, M.P. 159.5-160; [0:];3 +145.6- (c.=l, chloroform).

Example 11 A solution of 12 g. of lla-mesyloxy-progesterone in 300 ml. of methylene chloride/ ethyl acetate (2:1) was treated with ozone at 70 until the solution became blue in color. The excess of ozone was removed by bubbling oxygen through the reaction mixture for five minutes. Methylene chloride was then removed under reduced pressure, and the solution diluted with ethyl acetate to 200 ml. After addition of 12 ml. of 30 percent aqueous hydrogen peroxide, the reaction mixture was 26 then allowed to stand overnight at 2 (i.e., in the refrigerator), then evaporated to a volume of 75 ml. and diluted with ml. of benzene. The aqueous solution, obtained by extraction with 8 portions of 75 ml. 2 N sodium carbonate followed by combining the aqueous extracts was acidified with cold concentrated hydrochloric acid to pH 2 and extracted with methylene chloride. This extract was dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue crystallized when triturated with ether-acetone mixture, yielding crude lla-mesoxy 5,20 dioxo-3,5-seco-A-norpregnan-3-oic acid. After recrystallization from acetonepetroleum ether, M.P. 152-453"; +47.9 (c.=1, chloroform).

Example 12 A solution of 6 g. of lla-mesoxy-5,20-dioxo-3,5-seco- A-nor-pregnan-3-oic acid in ml. of methanol was mixed with a solution of 1.5 g. of sodium carbonate in 55 ml. of water. The mixture was then transferred into a 1 liter sublimation flask, and evaporated to dryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetate is added, and after closing the top part of the apparatus, this mixture was pyrolyzed at 290 and 0.02 mm. for four hours. The product, which collects on the cold finger, was dissolved in ether and filtered. The filtrate was then evaporated to dryness. Purification of the residue by chromatography on a 40 g. silica-gel column (benzene eluant) gave crystalline desA-pregn-9-ene-5,20-dione; MP. Ill-113 (after recrystallization from ether). +56.8 (c.=0.25 percent in methanol).

Example 13 To a solution of 1.2 g. of desA-pregn-9-ene-5,ZO-dione in 20 ml. of methanol maintained at 0, there was slowly added a cooled solution of 1.2 g. of sodium borohydride in 22 ml. methanol, and the resultant mixture was left for 72 hours at 0. It was then diluted with 100 ml. of water and extracted with four 100 ml. portions of chloroform. The extract was dried over anhydrous sodium sulfate and evaporated in vacuo, yielding a colorless oily product. This product was dissolved in 250 ml. of chloroform and 6 g. of manganese dioxide was added to the solution which was then stirred for 72 hours at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a silica-gel column and the eluates with 5 percent ethyl acetate in benzene, after concentration gave crystalline ZOB-hydroxy-desA-pregn-9-en-5-one which upon recrystallization from methylene chloride-petroleum ether formed colorless needles, M.P. 122123; [111 -33 (c.=0.5, absolute ethanol).

Example 14 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of 95 percent ethanol and 5.25 ml. of 2 N aqueous sodium hydroxide was hydrogenated at room temperature and atmospheric pressure. To this was added a solution of 262 mg. of 20fl-hydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 percent ethanol, and the reaction mixture then hydrogenated at room temperature and atmospheric pressure. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, and the catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. To the residue was added 1 ml. of glacial acetic acid, and it was then dissolved in 1 liter of ether. The cloudy solution was washed with 2 N aqueous sodium carbonate solution, then with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. It yielded a colorless oil, which was chromatographed on a silica-gel column using 1 percent ethyl acetate in benzene as the elutant. First eluted was ZOfl-hydroxy-lOwdeSA-pregnan-S-One, M.P. 107l08 after recrystallization from methylene chloride/petroleum ether.

27 (in methanol); [(115 [11140 89; [M1350 -274; [11 05 [1!]300 1165.

Further elution yielded 20B-hydroxy-9fl,IOB-desA-pregnan-S-one as a colorless oil. R.D. (in methanol); [M 1400 1350 1310 Example 15 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 2 ml. of 3 N aqueous hydrochloric acid and 18 ml. 95 percent ethanol was hydrogenated at room temperature and atmospheric pressure. A solution of 262 mg. of ZOB hydrOxy-deSA-pregn- 9-en-5-one in 5 ml. of absolute ethanol was introduced into the hydrogenation flask, and the reaction mixture was then hydrogenated at room temperature and atmospheric pressure. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate neutralized with 2 N aqueous sodium hydroxide solution. An excess of 5 ml. of 2 N aqueous sodium hydroxide was added and the solution allowed to stand overnight. Ethanol was then removed by evaporation at reduced pressure, and after addition of 1 mi]. of glacial acetic acid, it was extracted with 1 liter of ether. The extract was washed with 2 N aqueous sodium carbonate solution, then with water, dried and concentrated in vacuo. It gave a colorless oil, which was chromatographed on a silica-gel column using 2 percent ethyl acetate in benzene as the eluant. The first fractions of the eluate yielded, upon concentration, ZOfi-hydroxy- 10a-desA-pregnan-5-one. From the immediately subsequent fraction, 20,8-hydroxy-9 8, IOB-desA-pregnan-S-one was obtained. Both products were identical with the same compounds obtained in Example 14.

Example 16 ZOB-hydroXy-QB,10a-pregn-4-en-3-one is prepared by condensation of 3-hydroxy-95,IOp-desA-pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5. The product melts at 176.5178.5; [Q 143 (chloroform).

Example 17 A medium is prepared of 20 g. of Edamine enzymatic digest of lactalbumin, 3 g. of corn steep liquor and 50 g. of technical dextrose diluted to 1 liter with tap water and adjusted to a pH of 4.3-4.5. Twelve liters of this sterilized medium is inoculated with Rhizopus nigricans minus strain (A.T.C.C. 6227b) and incubated for 24 hours at 28 using a rate of aeration and stirring such that the oxygen uptake is 6.3-7 millimoles per hour per liter of Na S0 according to the method of Cooper et a1., Ind. Eng. Chem., 36, 504 (1944). To this medium containing a 24 hour growth of Rhizopus nigricans minus strain, 6 g. 17e-acetoxy-progesterone in 150 ml. of acetone is added. The resultant suspension of the steroid in the culture is incubated under the same conditions of temperature and aeration for an additional 24 hour period after which the beer and mycelium are extracted. The mycelium is then filtered, washed twice, each time with a volume of acetone approximately equal in volume to the mycelium, extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride extracts including solvent are then added to the beer filtrate. The mixed extracts and beer filtrate are then extracted successively with 2 portions of methylene chloride, each portion being /2 the volume of the mixed extracts and beer filtrate, and then with 2 portions of methylene chloride, each portion being M1 the volume of the mixed extracts and beer filtrate. The combined methylene chloride extracts are then washed with 2 portions of a 2 percent aqueous solution of sodium bicarbonate, each portion being A the volume of the combined methylene chloride extracts. The methylene chloride extracts are then dried with about 3-5 g. of anhydrous sodium sulfate per liter of solvent, and then 17OC-aCtOXy-5,20-diOX0-1ltX-ITICSOXY A nor 3,5- secopregnan-S-oic acid is prepared by ozonolysis of 17aacetoxy-lla-mesoxy-progesterone, according to the procedure of Example 11.

Example 19 17a-acetoxy desA-pregn-9-ene-5,ZO-dione is prepared from 17a-acetoxy-5,20-dioxo-1la-mesoxy A nor 3,5- secopregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 20 17a-acetoxy-20B-hydroxy-desA-pregn-9-en-5-one is prepared from 17a-acetoxy-desA-pregn-9-en 5,20 dione by reduction and reoxidation according to the procedure of Example 13.

Example 21 17a-acetoxy-205-hydroxy-9,B,IOB-desA-pregnan-S-one is prepared from 17a-acetoxy-20;3-hydroxy-desA pregn- 9-en-5-one by hydrogenation under acidic conditions in the presence of rhodium catalyst, according to the proce dure of Example 15.

Example 22 17a acetoxy 20p hydroxy-95,10a-pregn4-en-3-one is prepared by condensing methyl vinyl ketone with 17aacetoxy 20B-hydroxy-9fi,10,8-desA-pregnan-5-one according to the procedure of Example 5 except instead of conducting the condensation in absolute ethanol and catalyz ing it with sodium ethoxide, the condensation is conducted in acetic acid and is catalyzed with ptoluene sulfonic acid.

Example 23 20fi-hydroxy-4-methyl-9fl,10m-pregn-4-en-3-one is prepared by condensing 20fl-hydroxy-9fl,l(lfi-desA-pregnan- 5-one and ethyl vinyl ketone according to the procedure of Example 5.

Example 24 17fl-hydroxy-5-oxo-3,S-seco-A-nor-androstan-3-oic acid is prepared by ozonolysis of testosterone according to the procedure of Example 1.

Example 25 175 hydroxy 10a: desA-androstan-S-one and 17B-hydroxy-IOfl-desA-androstan-Scne are prepared from 17 3- hydroxy-5-oxo-3,S-seco-A-norandrostan-B-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 26 17/3hydroxy-desA-androst-9-en-5-one is prepared from 17,8- hydroxy-10u-desA-androstan-5-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 26a DesA-androst-Qcne-S,17-dione is prepared from 17,3- hydroxy-desA-androst-9-en-5-one by oxidation of the latter with a 2 percent chromic acid solution in percent acetic acid. The soobtained desA-androst-9-ene-5,17- dione is recrystallized from cyclohexane and melts at 123- 123.5; [a] :+83 (c.=0.102l, dioxane).

29 Example 27 A solution of 236 mg. of 17 8-hydroxy-desA-androst-9- en-S-one in 40 ml. 95 percent ethanol and 5.25 ml. 2 N aqueous sodium hydroxide solution was hydrogenated with one mole equivalent of hydrogen over 236 mg. of prereduced 5 percent rhodium or alumina catalyst. After separation of catalyst, the solution was concentrated in vacuo to dryness, and the residue taken up in one liter of ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. From the residue l7fl-hydroxy-9B,l0,8- desA-androstan-S-one was obtained by crystallization. M.P. 144.5l45; [a] 22 (c.=0.103; dioxane). The Uri-acetate (i.e. 17;.1- acetoxy-9,8,lflfi-desA-androstan-S- one) is obtained by acetylation of testosterone followed by ozonolysis, pyrolysis, bromination and dehydrobromination, and reduction according to the methods of Exam les 24, 25, 26 and 27 respectively, and melts at 118- 119"; [(11 -28 (c.=0.103; dioxane).

Example 28 A solution of 238 mg. of l7fi-hydroxy-9/110fi-desA- androstan-S-one, 1 ml. of ethylene glycol and catalytic amount of p-toluene sulfonic acid in 100 ml. of anhydrous benzene was slowly distilled until no more water was coming over. The solution was then concentrated in vacuo to a small volume, and 17B-hydroxy-9,8,10,B-desA- androstan-S-one S-ethylene ketal was obtained from the residue by crystallization. M.P. 115116; 9 (c.:0.0987; dioxane).

Example 29 To a solution of 282 mg. of 17B-hydroxy-9,3,l05-desA- androstan-S-one S-ethylene ketal in 50 ml. of methylene chloride was added 1 equivalent of 2 percent chromic acid in pyridine, and the reaction mixture then stirred overnight. The reaction mixture was then washed with percent aqueous sodium hydrogen sulfite, 2 N aqueous sodium carbonate, water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. Crystallization of the residue gave 9,8,10,8-desA-androstane-5,l7-dione S-mono-ethylene ketal. Splitting of the ketal in acetone solution in the presence of a catalytic amount of p-toluene sulfonic acid gives 9B,10;8-desA- androstane-5,I7-dione which melts, after recrystallization from cyclohexane, at 77.5-78; [111 +55 (c.=0.107; dioxane).

Example 30 To a preformed solution of one mole equivalent of prop-l'-inyl lithium in 100 ml. of anhydrous liquid ammonia was added tetrahydrofuran solution of 200 mg. of 9,8,IOfi-desA-androstane-S,17-dione S-mono-ethylene ketal, and the reaction mixture stirred for two hours. After addition of one gram of ammonium chloride, cooling was discontinued, and the reaction mixture allowed to evaporate. The residue was extracted with methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in 20 ml. of acetone and the catalytic amount of p-toluenesulfonic acid added, and the solution was refluxed for two hours, then poured in water and extracted in methylene chloride. The methylene chloride extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue gave l7a-(prop-1'-inyl)-17fi-hydroxy-9l3-IOB-desA- androstan-S-one.

Example 31 17a (prop 1' inyl)-l7fi-hydroxy-9fi,IOa-andmstan- 4-en-3-0ne is prepared by condensing methyl vinyl ketone with 1711 (prop l inyl)-17fl-hydroxy-9 3J0fl-desA- androstan-S-one according to the procedure of Example 5. The product melts at 164165.

Example 32 To a stirred solution of one mole equivalent of Z-methyl-prop-Z-enyl magnesium bromide in ml. of ether at room temperature was added dropwise a solution of 280 mg. of 9B,IOB-desA-androstane-S,l7-dione S-mono-ethylene ketal in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for one hour. After cooling in an icesalt bath, a saturated solution of sodium sulfate was slowly added to decompose the Grignard complex. This was followed by addition of anhydrous sodium sulfate. The solution was separated by filtration and concentrated in vacuo to dryness. The solution of the residue and of a catalytic amount of p-toluene sulfonic acid in 20 ml. of acetone was refluxed for two hours, then poured in water and extracted in methylene chloride. Methylene chloride extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. From this residue 17a-(2 methyl prop 2 enyl) l7fl-hydroxy-95,l0fi-desA- androstan-S-one was obtained.

Example 33 17a (2' methyl prop 2'-enyl)-17B-hydroxy-95, 10a-androst-4-en-3-one is prepared from 17a-(2'-methylprop 2'-enyl)-l7;9-hydroxy-9;3-IOB-desA-androstan-S-one by condensation of the latter with methyl vinyl ketone according to the procedure of Example 5. The product melts at l06108.

Example 34 acetoxy-ZO-ethylenedioxy-pregn-4-en-3-one is prepared by acetylation of 16a-hydroxy-20-ethylenedioxypregn-4-ene-3,20-dione with one equivalent of acetic anhydride in pyridine solution at room temperature for 2 hours, followed by concentration to dryness in vacuo. 16aacetoxy ZO-ethylenedioxy-5-oxo 3,S-seco-A-norpregnan- 3-oic acid is prepared by ozonolysis of lfinr-HCCIOXY-ZO-flthylenedioxy-pregn-4-en-3-one according to the procedure of Example 1.

Example 35 16a: acetoxy 2O ethylenedioxy-IOtI-desA-pregnan- 5-one and 16a acetoxy-20-ethylenedioxy-IOB-desA- pregnan-S-one are prepared from 16a-acetoxy-20ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis (according to the procedure of Example 2) and reacetylation with acetic anhydride and pyridine.

Example 36 16a: acetoxy 20 ethylendioxy-desA-pregn-9-en-5- one is prepared from 160: acetoxy-ZO-ethylendioxy-10adesApregnan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 37 160: acetoxy-20-ethylenedioxy-9r3,10fl-desA-pregnan-5- one is prepared from 16oz acetoxy-ZO-ethylenedioxydesA-pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

Example 38 169: hydroxy 20 ethylenedioxy-9fi,10a-pregn-4-en- 3-one is prepared by condensing 16a acetoxy-ZO-ethylenedioxy desA-9fl,lOfl-pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5.

Example 39 3B hydroxy 16a methyl-pregn-S-en-2D'one ethylene ketal is prepared by ketalization of 3,3 hydroxy-l6a-methyl-pregn-5-en-20-one in benzene solution with ethylene glycol using p-toluenesulfonic acid as catalyst. Pyridinechromic acid oxidation of the so-0btained 3B-hydroxy-l6amethyl-pregn-S-en-ZO-one ethylene ketal yields lfia-methyl-20-ethylenedioxy-pregn-4-en-3 one. 160: methyl-20- ethylenedioxy 5 oxo-3,5seco-A-norpregnane-3-oic acid is prepared by ozonolysis of 16a-methyl-20-ethylene-di- 31 oxy-pregn-4-en-3-one according to the procedure of Example 1.

Example 40 16a methyl 20 ethylenedioxy-a-desA-pregnan-5- one and 16a methyl 2O ethylenedioxy-IOB-desA-pregnan-S-one are prepared from 16a methyl-ZO-ethylenedioxy 5-oxo-3,S-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, accordng to the procedure of Example 2.

Example 41 16a methyl--ethylenedioxy-desA-pregn-9-en-5-one is prepared from 160: methyl 20 ethylenedioxy-wudesA pregnan-5-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 42 16a methyl 2O ethylenedioxy 95,105 desA- pregnan-S-one is prepared from 16a-methyl-20-ethylenedioxy-desA-pregn-9-en-5-one hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

Example 43 16a-methyl 20 ethylenedioXy-9 8,l0a-pregn-4-en-3- one is prepared by condensing l6ot-methyl-20-ethylenedioxy-9pr,10,B-desA-pregnan-5-one with methyl vinyl ketone, according to the procedure of Example 5.

Example 44 21 acetoxy 11a hydroxy-20-ethylenedioxy pregn- 4 en 3 one is prepared by microbiological treatment of 2l-acetoxy-2D-ethylene dioxy pregn 4 en-3-one, according to the procedure of Example 17. 21-acetoxy- 11a-mesOXy-ZO-ethylenedioxy 1 pregn 4 en-3-one is prepared by treatment of ZI-acetoxy-lIa-hydrOXy-ZO-ethylenedioxy-pregn-4-ene-3-one with methanesulfonyl chloride, according to the procedure of Example 10.

Example 45 21-acetoxy-1lm mesoxy-20-ethylenedioxy-S-oxo 3,5- seco A norpregnan 3 oic acid is prepared by ozonolysis of 21-acetoxy-1 lrx-mesoxy-20-ethylenedioxy-pregn-4- en-3-one, according to the procedure of Example 11.

Example 46 2l-acetoxy20-ethylenedioxy-9B-1OB desA pregnan-S- one is prepared from 21-acetoxy-ZD-ethylenedioxy desA- pregn-9-enS-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15.

Example 48 21 hydroxy 20 ethylenedioxy 95,10a-pregn-4-en- 3-one is prepared from 21 acetoxy-ZO-ethylenedioxy- 9B,lOfi-desA-pregnan-S-one by condensing the latter with methyl vinyl ketone, according to the procedure of Example 22.

Example 49 1la-mesoxy-l6a,l7a-isopropylidenedioxy progesterone is prepared by treatment of 1la-hydroxy-16a,17ot-isopropylidenedioxy-progesterone with methane sulfonyl choride, according to the procedure of Example 10.

Example 50 5,20-dioxo-lla-mesoxy-l6a,l7a isopropylidenedioxy- 3,5-seco-A-norpregnan 3 oic acid is prepared by ozonolysis of 1lot-mesoxy-16a,17a-isopropylidenedioxy-progesterone, according to the procedure of Example 11.

Example 51 16a,l7ot-isopropylidenedioxy desA pregn 9 en- 5,20 dione is prepared from 5,20 dioxo 11a mesoxy- 16a,170c-1SOIJTOPyIidEIICdiOXy-3,5 seco A norpregnan- 3-oic acid by conversion of the latter to its sodium salt, followed by pyrolysis according to the procedure of Example 12.

Example 52 20,8-hydroxy l6a,17ot isopropylidenedioxy desA- pregn-9-en-5-one is prepared from 1601,1711: isopropylidenedioxydesA-pregn-9-ene 5,20 dione by reduction and reoxidation, according to the procedure of Example 13.

Example 53 20,6 hydroxy 1601,17 isopropylidenedioxy-9;8,1013- desA pregnan-S-one is prepared from 20 5 hydroxy- 16a,17a-isopropylidenedioxy-desA-pregn 9 en 5 one by hydrogenation according to the procedure of Example 14.

Example 54 20,8 hydroxy l6a,17a-isopropylidenedioxy 913,100:- pregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 20,8-hydroxy-16z,17a isopropylidenedioxydesA-9 8,103 pregn 5 one according to the procedure of Example 5.

Example 55 7a,17a-dimethyl 17B hydroxy 5 oxo 3,5-seco- A-norandrostan-3-oic acid is prepared from 7a,]7a-dimethyl testosterone by ozonolysis of the latter, according to the procedure of Example 1.

Example 56 7a,17a dimethyl-l7B-hydroxy-10a desA androstan- S-one and 7a,17a-dimethy1-17B-hydroxy-IOB-desA-androstan-S-one are prepared from 711,17 dimethy1-l7fl-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 57 7a,17a-dimethyl 17B hydroxy-desA-androst 9 en- 5-one is prepared from 70L,17oc dimethyl-l7B-hydroxy- IOa-desA-androstan-S-une by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 58 7a, 17nt-dimethyl-17fi-hydroxy-desA-9B,10p androstan- S-one is prepared from 70,17u, dimethyl-17 3-hydroxydesA-androst 9 en 5 one by hydrogenation in the presence of a rhodium catalyst, according to the procedure of Example 4 Example 59 7a,l71x-dimethyl 9)3,l0oz testosterone is prepared from 70:,17m dimethyl 17B hydroxy-desA-9B,10,8-androstan- S-one by condensing the latter with methyl vinyl ketone, according to the procedure of Example 5.

Example 60 1la-mesoxy-l7ot-methyl-progesterone is prepared from 1la-hydroxy-l7a-methyl-progesterone by treatment of the latter with methane sulfonyl chloride, according to the procedure of Example 10.

Example 61 11a mesoxy-l7tx-methyl-5,20-dioxo 3,5 seco-A-norpregnan-3-oic acid is prepared f om lla-mesoxy-lhmethyl-progesterone by ozonolysis of the latter, according to the procedure of Example 11.

Example 62 l7a-methyl-desA-pregn-9-ene-5,20-dione is prepared from lla-mesoxy 17a methyl-5,20-dioxo-3,5-seco-A- norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 63 20fl-hydroxy 17a methyl-desA-pregn-9-en-5-one is prepared from 1711 methyl desA-pregn-9- n-5,20-dione according to the procedure of Example 13.

Example 64 ZOfl-hydroxy 17a methyl-95,105 desA pregnan-S- one is prepared from 17a-methyl-20fi-hydroxy-desA- pregnan 9 ene-S-one according to the procedure of Example 15.

Example 65 20B hydroxy-17a-methyl-9/3,10a-pregn-4-en-3-one is prepared by condensing 17a-methyl-20fi-hydroxy-9fl-10,6- desA-pregnan-S-one with methyl vinyl ketone, according to the procedure of Example 4.

Example 66 A solution of 12.8 g. of 17u-methyltestosterone in 200 ml. of methylene chloride and 100 ml. of ethyl acetate was ozonized for 1 hour and 5 minutes at 70 (acetone- Dry Ice bath) until a blue color developed. After oxygen was bubbled through, the solution was then concentrated at room temperature in vacuo. The residue was dissolved in 400 ml. of acetic acid, and after addition of 30 ml. of 30% hydrogen peroxide, the solution was left overnight at It was then evaporated to dryness in vacuo, the residue taken up in ether, and the ether solution extracted with 2 N aqueous sodium carbonate (12X 50 ml.). The combined carbonate extracts were cooled in ice, and acidified with concentrated hydrochloric acid. The aqueous suspension of precipitated organic acid was extracted with methylene chloride, this extract was washed with water, dried over anhydrous sodium sulfate and evaporated giving as a colorless crystalline material 17(3-hydroxyl7e-methyl-5-oxo-3,5 seco A-nor-androstan-B-oic acid. After recrystallization from acetone-hexane, it melted at 195-197, [a] =9.8 (c.=l.0 in chloroform).

Example 67 A solution of 10 g. of 17fi-hydroxy-l7a-methyl-5-oxo- 3,5-seco-A-nor-androstan-S-oic acid in 250 ml. of methanol was made alkaline to phenolphthalein with sodium ethoxide, and evaporated to dryness. The residual powdery sodium salt was mixed well with 32 g. of sodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), and the mixture heated at 290 in vacuo for 4 hours. After cooling to room temperature, a large excess of water was added, and the resultant suspension extracted with 2 liters of ether. The ether extract was washed with water, aqueous 2 N sodium carbonate solution, and again with water, dried and evaporated. This gave a syrupy residue, which by thin layer chromatograms and infrared spectra consisted of 17fi-hydroxy-17a-methyl-10a-desA- androstan-S-one as the major and l7p3-hydroxy-l7a-methyl-IOfi-desA-androstan-S-one as the minor product.

Three additional pyrolyses were performed as described above, and the combined products so-obtained was chromatographed on a 850 g. silica gel column, using ethylacetate in benzene as the eluent. This chromatography yielded 17,8-hydroxy-17e-methyl 10adesA-androstan-S-one, which after recrystallization from petroleum ether melted at 9697, [a] =23.2 (c.=0.5 in chloroform).

Further eluates of the column gave product, 17,8-hydroxy-17a-methyl-IOfi-desA-androstan-S-one which, when 34 recrystallized from ether, melted [a] =l9.8 (c.=0.5 in chloroform).

To a solution of 2.2 g. of the mixture of l7fl-hydroxy- 17a-methyl-IOa-desA-andrustan 5 one and 17B hydroxy-l7a-methyl-lOB-desA-androstan-S-one (obtained by the above pyrolysis procedure) in 50 ml. of absolute ethanol were added 20.1 ml. of a solution prepared by dissolving 2.48 g. of sodium metal in 250 ml. of absolute ethanol. The reaction mixture was stirred overnight at room temperature. It was then acidified with 2 ml. of glacial acetic acid, and evaporated to dryness. The residue was extracted in ether (1 liter) and the ether extract washed with water, dried, and evaporated. The residue was crystallized from petroleum ether giving a quantitative yield of l7fl-hydroxy-l7u-methyl-IOa-deSA-androstan- S-one.

Example 68 To a solution of 11.2 g. of l7fl-hydroxy-17a-methyl- 10a-desA-androstan-5-one in 1260 ml. of anhydrous ether, stirred and cooled in an ice-salt bath, were added first several drops of 30% hydrogen bromide in acetic acid, then dropwise a solution of 7.16 g. of bromine in 20 ml. of glacial acetic acid. The rate of addition of the bromine solution was synchronized with the rate of disapperance of excess bromine. After bromination was complete, 53 ml. of 10% sodium hydrogen sulfite solution and 53 ml. of aqueous 2 N sodium carbonate solution were added to the reaction mixture while stirring. The ether layer was then separated, washed with water, dried, and evaporated to dryness in vacuo. The residue was dissolved in 250 ml. of dimethylformamide, and heated with 7.5 g. of lithium carbonate at 100 for 45 minutes. After cooling, 2 liters of ether were added and the ether solution washed with water, 1 N hydrochloric acid, and then again with water, dried and evaporated. The residue was dissolved in 200 ml. of glacial acetic acid, 12.6 of sodium acetate and 12.6 g. of zinc powder were added and the mixture heated for ten minutes at After cooling to room temperature, the reaction mixture was filtered, and evaporated. The residue was dissolved in ethylacetate, and washed with saturated sodium bicarbonate solution, then with water, dried and evaporated. The so-obtained residue was chromatographed on a silica gel column using 10% ethylacetate in benzene as the eluent which gave first 17phydroxy- 1 7 e-methyll Oa-dCSA-EtlldfOStEtn-S-Onfi, followed by 173 hydroxy-17a methylalesA-androst-9-en-5one. After recrystallization from ether, the latter compound melted at 103-104", [a] =63.2 (c. =0.5 in chloroform).

Example 69 A suspension of 1.25 g. of 5% rhodium on alumina catalyst in a mixture of 130 ml. of 95% ethanol and 26 ml. of 2 N sodium hydroxide was prereduced. To this was then added a solution of 1.25 g. l7B-hydroxy-l7amethyl-desA-androst-9-en-5-one in 75 ml. of 95 ethanol, and then the mixture was hydrogenated at atmospheric pressure and room temperature. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was removed by filtration, and the filtrate evaporated in vacuo. To the residue 5 ml. of glacial acetic acid was added, the so-formed mixture then dissolved in 2 liters of ether, and the resultant cloudy solution was washed with water, then dried and evaporated. The residue was dissolved in 5 0 ml. of methylene chloride and oxidized with 5 ml. of 2% chromic acid in acetic acid until green color of reaction mixture. After then being washed with sodium hydrogen sulfite solution 2 N sodium carbonate solution and water, the reaction mixture was dried over sodium sulfate and evaporated. The residue was chromatographed very slowly on a 50 g. silica gel column, with 5% ethylacetate in benzene, and followed with thin layer chromatography. First, l7B-hydroxy-l7amethyl-9a,10a-desA-androstan-5-one was eluted. After a minor amount of mixed material, 17 8-hydr0xyl7u- 35 methyl-9,8,IOfl-desA-androstan-S-one was eluted. After recrystallization from ether-petroleum ether, it melted at 94-96".

Example 70 l7a-methyl-9p,lOu-testosterone is prepared from 170:- methyhl7tfl-hydroxy-desA-9 3,lOti-sndrostan-S-one by condensation of the latter with methyl vinyl ketone, according to the procedure of Example 5. The product melts at 128-129".

Example 71 A solution of 6 g. of l1m2()p-diacetoxy-pregn-4-en-3- one in 100 ml. methylene chloride and 50 ml. of ethylacetate was ozonized at 70. After methylene chloride was removed by distillation in vacuo, the residual solution was diluted to l(){) ml. with ethylacetate. To this ml. of 30 percent hydrogen peroxide was added and left overnight at room temperature. The reaction mixture was concentrated to dryness in vacuo, the residue taken up in 1 liter of ether. and the resulting solution extracted times with 50 ml. portions of 2 N aqueous sodium carbonate. The carbonate extract was then acidified with ice-cold concentrated hydrochloric acid. The precipitated product was separated by filtration, and crystallized to give 11:1,205 diacetoxy-5 oxo-3,5-seco-A-nor-pregan-3 oic acid.

Example 72 A methanolic solution of 5 g. of 1111,2Dl3-dl3C6t0XY-5- oxo-3,5-seco-A-nor-pregnan-3-oic acid was treated with one-half mole equivalent of sodium carbonate, and evaporated to dryness in vacuo. Potassium acetate (5 g.) was added to the residue which was the pyrolyzed at 295 and 0.02 mm. The sublimate was chmmatographed on a silica-gel column to give 11a,20t3diacetoxy-IOp-desA- pregnan-S-one.

Example 73 Bromination and dehydrobro mination starting with 1la,20,B-diacetoxy-lOfl-desA-pregnamS-one according to the procedure of Example 3, gave 11a,20B-diacetoxydesA-pregn-9-en-5-one.

Example 74 Hydrogenation of l1a,20fi-diacetoxy-desA-pregn-9-en 5-one in ethanolic hydrochloric acid over 5 percent rhodium on alumina catalyst at room temperature and atmospheric pressure according to the procedure of Example 15 gave lla,20fi-di8.C6tOXy-9B,lOtB-deSA-plcgflafl- 5-one.

Example 75 1101,2013 diacetoxy-9B,10fi desA-pregnan-5-one was hydrolyzed in methanol solution with one mole equivalent of potassium carbonate to give lla,20,8 dihydroxy-9fi; 10,8-desA-pregnan-5-one.

Example 76 Condensation of 1111,205 dihydroxy 9;3,10B desA- pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5 gave 1la,2(lfl-dihydroxy-9fi,1[)apregn-4-en-3-one.

Example 77 A solution of 3 g. of 17a-ethyl-l7t3-hydroxy-androsta- 1,4-dien-3-one in 75 ml. of methylene chloride and ml. of ethyl acenate was ozonizecl at 70 till it became blue. After evaporation to dryness, the residue was dissolved in 100 ml. of glacial acetic acid containing 5 m1. of percent hydrogen peroxide, and set at room temperature for 2 days. The reaction mixture was concentrated to dryness and the residue dissolved in one liter of ether. The ether solution was then extracted 10 times with 25 ml. portions of aqueous 2 N sodium carbonate solution, and the carbonate extracts were acidified with ice-cold concentrated hydrochloric acid. The non-crystalline precipitate containing 17a ethyl 175 hydroxy 10a carboxydesA androstan 5 one was separated by filtration and dried, then dissolved in 135 ml. of absolute ethanol, and after addition of 9 ml. of aqueous 2 N sodium hydroxide, boiled for 1 hr. The reaction mixture was concentrated in vacuo to a small volume, and diluted with 1750 ml. of ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The residue was crystallized from ethenpetroleum ether, to give 17:! ethyl 175 hydroxy 10adesA-androstan-S-one, M.P. 8990.

Example 78 3 (17B hydroxy 5 oxo 3,5 seco A nor androstan 17a yl 3 oic acid) propionic acid lactone is prepared by ozonolysis of 3 (3 oxo 175 hydroxyandrost-4-en-17a-y])-propionic acid lactone, according to the procedure of Example 1.

Example 79 3 (17B hydroxy 5 oxo 10o: desA androstan- 17a yl) propionic acid lactone and 3 (17o hydroxy- 5 oxo 10,8 desA androstan 17a 4 yl) propionic acid lactone are prepared from 3 (17,6 hydroxy 5 oxo- 3,5 seco A nor androstan 17a yl 3 oic acid)- propionic acid lactone by conversion of the latter to its sodium salt followed by pyrolysis, according to the proce dure of Example 2.

Example 80 3 (17B hydroxy 5 oxo desA androst 9 en- 17a-yl)-propionic acid lactone is prepared from 3-(175- hydroxy 5 oxo 10a desA androstan 17a yl)- propionic acid lactone by bromination followed by de hydrobromination, according to the procedure of Exampie 3.

Example 81 3 (17 9 hydroxy 5 oxo 95,105 desA androstan- 17a-yl)-propionic acid lactone is prepared from 3-(175- hydroxy 5 oxo desA androst 9 en 17a yl)- propionic acid lactone by hydrogenation in the presence of a rhodium catalyst, according to the procedure of Example 4.

Example 82 3 (17p hydroxy 3 oxo 95,100: androst 4 en- 17a-yl)-propionic acid lactone is prepared by condensing 3 (17p hydroxy 5 oxo 95.105 desA androstan- 17a-yl)-propionic acid lactone with methyl vinyl ketone, according to the procedure of Example 5.

Example 83 17oz,2(];20,21 bis methylenedioxy 11oz mesyloxypregn 4 en 3 one is prepared by treatment of 1711,20; 20,21 bis methylenedioxy lla hydroxy prcgn 4- en-3-one with methanesulfonyl chloride according to the procedure of Example 10.

Example 84 l7a,20;20,21 bis methylenedioxy 11a mesyloxy- 5 oxo 3,5 seco A norpregnan 3 oic acid is prepared by ozonolysis of 17e,20;20,2l bis methylenedioxy 11a mesyloxy pregn 4 en 3 one according to the procedure of Example 11.

Example 85 17a,20;20,21 bis methylenedioxy desA pregn 9- en 5 one is prepared from l7u,20;20,21 bis methylenedioxy Ila mesyloxy 5 oxo 3,5 seco A norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 86 17a,20;20,2l bis methylenedioxy 9 8.1071 desA- pregnan 5 one is prepared from l7 x,20;20,2l his;

methylenedioxy desA pregn 9 en one by hydrogenation in the presence of a rhodium catalyst according to the procedure of Example 14.

Example 87 l7a,20;20,2l bis methylenedioxy 918.1011 pregn 4- en-3-one is prepared by condensing methylvinyl ketone with 17a,20;20,2l bis methylenedioxy 96,1013 desA- prenan-S-one, according to the procedure of Example 5.

Example 88 205 hydroxy 9fl,l()a pregna 1,4 dien 3 one was prepared by condensation of 205 hydroxy 9 9,105- desA pregnan 5 one with 1 equivalent of methyl ethinyl ketone in boiling benzene solution, catalyzed by sodium hydride.

Example 89 One ml. of Jones reagent (0.004 mole CrO is added to 200 mg. of 17fi-hydroxy-9{3,lOB-desA-androstan-S-one in 20 ml. of acetone at The mixture is then left for minutes at room temperature, and 5 ml. of ethanol then added. The resulting suspension is evaporated to dryness in vacuo, water is added to the residue and the undissolved moiety taken up in ether. The ether phase is then washed with a solution of sodium bicarbonate and then with water, dried over sodium sulfate and evaporated to dryness. There is so obtained an oil which crystallizes upon the addition of a small portion of petroleum ether. The so-obtained crystals of 9B,l0)3-desA-androstane 5,17-dione melt, after recrystallization from cyclohexane, at 77.5-78; [a] +55 (c.=0.107, dioxane); R.D. in dioxane (c.=0.107%); A in m ([od value in degrees); 550(+70); 400(+297); 3S0(+798); 320(+2968) max; 300(+467); 299(0); 290(-1890).

Example 90 A solution of 250 mg. of 17,3-hydroxy-9BJ013-desA- androstan-S-one dissolved in 2.5 ml. of pyridine and 2.5 ml. of acetic anhydride, is left at room temperature for 18 hours. The mixture is then evaporated to dryness at 80/l1 mm., the residue taken up in ether, and the ether phase washed with 1 N hydrochloric acid, sodium bicarbonate and water, and then dried over sodium sulfate. After filtration and evaporation of the ether, the residue is then treated with a small quantity of petroleum ether yielding crystals of 17B-acetoxy-9;8,1ofl-desA-androstan- S-one which, upon recrystallization from methanol, melt at 118119; a 2s (c.:0.l03%, dioxane); R.D. in dioxane (c.=0.l03%): k in ma ([a]- value in degrees); 400(); 356(0); 350(+10); 313(+449) max.; 307(4-374) min.; 305(-|-380) max.; 303(+224); 293(0); 280(652).

Example 91 A solution of 250 mg. of 17B-acetoxy-9fi,l0,B-desA- androstan-S-one in 60 ml. of 95% methanol containing 144 mg. of potassium hydroxide is refluxed for 60 minutes. The resulting mixture is evaporated to dryness in vacuo, water added to the residue and the suspension extracted with ether. The ether phase is washed with water, dried over sodium sulfate, filtered off, the solvent removed and the crystalline residue then crystallized from a small volume of cyclohexane, yielding crystals of 17/8- hydroxy-9l3,IOB-desA-androstan-S-one which upon being recrystallized from ethylacetate melt at 144.5445"; [a] =2Z (c.:0.l03, dioxane), R.D. in dioxane (c.:0.l03); in ma ([a]:value in degrees); 400(7); 390(0); 350(+52); 3l3(+57l) max.; 307(+492) min.; 305(+504) max.; 300(+324); 293(0); 290(202).

Example 92 A solution of 10 g. of 1lB-formyloxy-androsta-l,4-diene-3,17-dione in 100 ml. of acetic acid was ozonized at 0 until thin layer chromatography did not show any starting material. The reaction mixture was then poured into 100 ml. of water and the mixture was then heated to 100 for 30 minutes. The mixture was then concentrated in vacuo and treated with 50 ml. of saturated sodium bicarbonate solution. The undissolved material was extracted with 100 ml. of ether. The extract was chromatographed on silica gel using methylene chloride. The eluates were concentrated and gave, on addition of hexane, 1lfl-formyloxy-l0g-desA-androstane 5,17 dione, M.P. ll7ll7.5 (recrystallized from acetone-cyclohexane), [a] =93 (dioxane).

Example 93 By hydrolysis of llB-formyloxy l0g-desA-androstane- 5,17-dione in 2% methanolic potassium hydroxide there is obtained 1lB-hydroxy-10-desA-androstan-5,l7- dione, which melts at 154; [a] +96 (dioxane).

Example 94 250 mg. of 1lfl-hydroxy-10-desA-androstane-5,l7-dione and 250 mg. of p-toluene sulfonic acid monohydrate in 20 ml. of benzene were refluxed in a nitrogen atmosphere for 6 hours. The reaction mixture was then washed with an aqueous solution of sodium bicarbonate and then with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was then chromatographed over silica gel (5 g.) in dichloromethane. Triturating the residue obtained from the first 250 ml. eluted, yielded crystals of desA-androst-9-ene-5,l7-dione, which upon recrystallization from cyclohexane melted at 123-l23.5.

Example 95 The compound, llfi-formyloxy-S,17-dioxo-3,5-seco-A- nor-androstan-3-oic acid is prepared from llp-formyloxy-androst-4-ene-3,17-dione by ozonolysis according to the procedure of Example 11. The so-obtained product melts at 220-221; [a] |l07 (dioxane).

Example 96 3.7 g. of the sodium salt of 1lfi-formyloxy-SJ7-dioxo- 3,5-seco-A-nor-androstan-3-oic acid and 12 g. of sodium phenylacetate are fused together in vacuo (0.1 torr). When the bath temperature reaches 220 the molten mass begins to decompose. The bath is then heated further (within 30 minutes) to a temperature of 290. Once this temperature has been reached the mixture is left for another 10 minutes at the initial pressure of 0.1 torr. The distilled material is then chromatographed over 30 g. of aluminum oxide (activity grade 3). Elution with a total of 200 ml. of petroleum ether-benzene (2:1), followed by evaporation of the solvent and trituration of the residue in the presence of petroleum ether, yields desA-androst-9-ene-5,l7-dione which upon recrystallization from cyclohexane melts at 123-1235"; [a] :+83 (c.=0.102l, dioxane).

Example 97 20B-acetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid is prepared by ozonolysis of 20,8-acetoxy-pregn-4-en-3-one according to the procedure of Example 1.

Example 98 A solution of 15.15 g. of 20,8-acetoxy-5-oxo-3,5-sec0- A-nor-pregnan-3-oic acid in 250 ml. of 75% methanol containing 10 g. of potassium hydroxide was refluxed for 2 hours. The methanol was then removed in vacuo and the residue was dissolved in 100 ml. of water. The solution was chilled to 0 and acidified to Congo red by the addition of 20% hydrochloric acid. There was thus obtained 20,3 hydroxy 5-oxo-3,S-seco-A-nor-pregnan-3-oic acid, M.P. 181182, [a] =l3 (dioxane).

A solution of 4.7 g. of 20p-hydroxy-5-oxo-3,5-seco-A- nor-pregnan-3-oic acid in 100 ml. of methanol was neutralized with 1 N sodium methylate solution against phenolphthaleine. The solution was then evaporated and the residue, consisting of 20,8-hydroxy-5-oxo-3,5-seco-A- nor-pregnan-B-oic acid sodium salt, was refluxed with 100 ml. of quinoline for 8 hours. The cooled mixture was poured on a mixture of 150 g. of ice and 100 ml. concentrated hydrochloric acid and extracted with ether. The ether extract was worked up and the oily residue was chromatographed on silica gel. Elution with methylene chloride gave la-desA-pregnane-5,20-dione, M.P. 126- 127 (crystallized from isopropyl ether), [a] :82 (dioxane). Elution with methylene chloride containing 1% acetone gave 205 hydroxy 10oz desA pregnan one, M.P. 104l04.5 (crystallized from ether-hexane), [a] =lO (dioxane). The fractions obtained with methylene chloride containing 5-l(]% acetone were evaporated and the oily residue was dissolved in 40 ml. of acetone. The solution was treated with 3 ml. of Jones reagent (0.004 mole CrO at and kept at the same temperature for 10 minutes. After the addition of 5 m1. of methanol, the solution was evaporated and the residue was diluted with water and extracted with ether. The ether extract was worked up and gave 10a-desA-pregnane-5,20- dione.

Example 99 20fi-hydroxy-desA-pregn-9-en-5-one is prepared from ZOfi-hydroxy-IOa-deSA-pregnan-S-One by bromination followed by dehydrobromination, according to the procedure of Example 3. The so-obtained product, after recrystallization from methylene chloride-petroleum ether, melts at 122123.

Example 100 5,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid is prepared by ozonolysis of progesterone according to the procedure of Example 1.

Example 101 lOa-deSA-pregna-5,20-dione and l0B-desA-pregnan-5, 20-dione are prepared from 5,20-dioxo-3,S-seco-A-norpregnan-3-oie acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 102 The compound, desA-pregn'9-ene-5,20-dione is prepared from l0a-desA-pregna-5,20-dione by bromination followed by dehydrobromination according to the procedure of Example 3. The so-obtained product, after recrystallization from ether, melts at ill-113.

Example 103 ml. of 0.8% potassium permanganate solution was added to a mixture of 11 g. of 20,8-tetrahydropyranyloxypregn-4-en-3-one, 500 ml. of an azeotropic mixture of tertiary butanol and water, 7 g. of potassium carbonate, ml. of water and 120 ml. of 7% sodium metaperiodate solution with vigorous stirring at room temperature. 250 ml. of 7% sodium metaperiodate and 20 ml. of 0.8% potassium permanganate solution were then simultaneously added within 15 minutes. To the so-obtained suspension, 220 ml. of 7% sodium metaperiodate solution and, in order to keep the mixture violet in color, 15 ml. of 0.8% potassium permanganate solution were then added in the course of 30 minutes. The mixture was then stirred for 90 minutes, filtered over a filter aid (Hyfio) and the residue was washed with 100 ml. of tert. butanol-water azeotrope. The filtrate was evaporated in vacuo at 50 and the residue diluted with 150 ml. of water. The solution was acidified with cold 20% hydrochloric acid to Congo red, and the resultant oily material taken up in 150 ml. of methylene chloride. The organic extract was washed with water, dried and evaporated and the residue was purified by filtration over silica gel using methylene chloride and methylene chloride containing l-2% ethanol as the elution agents. There was thus obtained ZOfl-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3oic acid as a viscous oil.

40 Example 104 To a solution of 35.8 g. of a mixture of 2001- and ZDfl-hydroxypregn-4-en-3-one in 500 ml. of anhydrous benzene, there were added 75 ml. of 1% p-toluenesulfonic acid in benzene and then 35 ml. of dihydropyran. The reaction mixture was allowed to stand at room temperature for 16 hours, washed with 2% aqueous sodium bicarbonate and water, dried and concentrated in vacuo at 11 mm. Hg and The residue consisting of 20aand ZOB-tetrahydropyranyloxy-pregn-4-en-3-one was dissolved in 2 liters of tert. butanol-water azeotrope followed by the addition of a solution of 33 g. of potassium carbonate in 80 ml. of water and 620 ml. of 7% aqueous sodium metaperiodate solution. To the reaction mixture there was first added with vigorous stirring at room temperature, 75 ml. of 0.8% potassium permanganate and thereafter simultaneously within 30 minutes 1350 ml. of 7% sodium metaperiodate solution and ml. of 0.8% potassium permanganate solution. Another 1080 ml. of 7% sodium metaperiodate solution and 100 ml. of 0.8% potassium permanganate solution were then added within 45 minutes. The reaction mixture was then stirred for 1 hour, filtered over a filter aid (Hyflo) and the residue was washed with 250 ml. of tert. butanol-Water azeotrope. The filtrate was evaporated, the residue taken up in 800 ml. of water and filtered. The alkaline filtrate was chilled to 0, acidified with cold 20% hydrochloric acid and extracted with methylene chloride. After working up, the extract afforded a mixture of ZOotand 20fl-tctrahydropyranyloxy-5-oxo-3,S-seco-A-nor-pregnan 3 oic acid as a viscous oil. This oil was dissolved in 300 ml. of methanol and neutralized with l N lithium methylate. The solution was evaporated to dryness in vacuo. The oily residue was dissolved in 300 ml. of benzene, evaporated again and dried at 11 mm. Hg and 100 for 2 hours. There was obtained a mixture of the lithium salts of 20aand 20(3-tetrahydropyranyloxy-S-oxo-3,5 seco A norpregnan-3-oic acid as an amorphous powder.

Example A solution of 9 g. of 20fi-tetrahydropyranyloxy-S-oxo- 3,5-seco-A-nor-pregnan-3oic acid in 100 ml. of methanol was neutralized with 1 N lithium methylate solution against phenolphthaleine, followed by evaporation in vacuo to dryness. The so-obtained residue was taken up in benzene, and the benzene evaporated yielding 20B- tetrahydropyranyloxy-S-oxo-3,5-seco A nor pregnan- 3-oic acid lithium salt as a semi-crystalline powder.

5 g. of this lithium salt, 7.5 g. of anhydrous sodium acetate and 7.5 g. of anhydrous potassium acetate were mixed and pyrolyzed at 0.020.1 mm. Hg and 290 for 4 hours. The distillate was chromatographed on silica gel using methylene chloride and methylene chloride containing O.5l% acetone as the elution agents. The fractions were evaporated and gave on treatment with ether-hexane 20B tetrahydropyranyloxy 10 desaA pregnan 5- one. M.P. 125.5-127" (crystallized from methanol) [u] :53 (dioxane).

The oily part of the evaporation residue containing besides the latter compound the compound ZOB-tetrahydropyranyloxy-ltlfi-desA-pregnan 5 one ethanol. After the addition of 10 ml. of water and 200 mg. of ptoluenesulfonic acid monohydrate, the solution was refluxed for 60 minutes and evaporated in vacuo. The residue was then treated with water and extracted with ether. The ether extract was Worked up and gave 20/8-hydroxy-10a-desA- pregnan-S-one, M.P. 104.5-105 (crystallized from etherhexane).

Example 106 250 mg. of ZOB-tetrahydropyranyloxy-lOa-desA-preg nan-5-one was dissolved in 8 ml. of ethanol and after the addition of 1 ml. of water and 15 mg. of p-toluenesulfonio acid monohydrate refluxed for 1 hour. The re- 

